Murine respirovirus#As an oncolytic agent

SeV replication occurs exclusively in the cytoplasm of the host cell. The virus is using its own RNA polymerase. One replication cycle takes approximately 12–15 hours with one cell yielding thousands of virions.{{cite book |vauthors=Cassano A, Rasmussen S, Wolf FR |chapter=Viral diseases |title=The laboratory rabbit, guinea pig, hamster, and other rodents |date=January 2012 |pages=821–837 |publisher=Academic Press |veditors=Suckow MA, Stevens KA, Wilson RP |id=American College of Laboratory Animal Medicine|isbn=978-0-12-380920-9}}

The virus is responsible for a highly transmissible respiratory tract infection in mice, hamsters, guinea pigs, rats,{{cite book |chapter=Chapter 17 - Paramyxoviridae and Pneumoviridae |date=2017 |title=Fenner's Veterinary Virology |edition=Fifth |pages=327–356 | veditors = MacLachlan NJ, Dubovi EJ |publisher=Academic Press|isbn=9780128009468 |doi=10.1016/B978-0-12-800946-8.00017-9 |s2cid=214757272}} and occasionally marmosets,{{cite journal | vauthors = Flecknell PA, Parry R, Needham JR, Ridley RM, Baker HF, Bowes P | title = Respiratory disease associated with parainfluenza Type I (Sendai) virus in a colony of marmosets (Callithrix jacchus) | journal =Laboratory Animals| volume = 17 | issue = 2 | pages = 111–113 | date = April 1983 | pmid = 6306336 | doi = 10.1258/002367783780959448 | s2cid = 7413539 | doi-access = free }} with infection passing through both air and direct contact routes. Natural infection occurs by way of the respiratory tract. In animal facility airborne transmission can occur over a distance of 5–6 feet as well as through air handling systems. The virus can be detected in mouse colonies worldwide,{{cite book |publisher=Elsevier|url=https://www.sciencedirect.com/book/9780123809209/the-laboratory-rabbit-guinea-pig-hamster-and-other-rodents |title=The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents |isbn=978-0-12-380920-9 | vauthors = Suckow MA, Stevens KA, Wilson RP |date=23 January 2012}} generally in suckling to young adult mice. A study in France reported antibodies to SeV in 17% of mouse colonies examined.{{cite book |vauthors=Nicklas W, Bleich A, Mähler M |chapter=Chapter 3.2 - Viral Infections of Laboratory Mice |date=2012-01-01 |doi=10.1016/B978-0-12-382008-2.00019-2 |title=The Laboratory Mouse |edition=Second |pages=427–480 |veditors=Hedrich HJ |publisher=Academic Press|isbn=9780123820082 |pmc=7150319}} Epizootic infections of mice are usually associated with a high mortality rate, while enzootic disease patterns suggest that the virus is latent and can be cleared over the course of a year. Sub-lethal exposure to SeV can promote long-lasting immunity to further lethal doses of SeV.{{cite journal | vauthors = López CB, Yount JS, Hermesh T, Moran TM | title = Sendai virus infection induces efficient adaptive immunity independently of type I interferons | journal =Journal of Virology| volume = 80 | issue = 9 | pages = 4538–4545 | date = May 2006 | pmid = 16611914 | pmc = 1472017 | doi = 10.1128/JVI.80.9.4538-4545.2006 }} The virus is immunosuppressive and may predispose to secondary bacterial infections.{{cite web |title=Sendai Virus |url=http://dora.missouri.edu/mouse/sendai-virus/ |work=Diseases of Research Animals}} There are no scientific studies, which were performed using modern detection methods, which would identify SeV as an infectious and decease causative for humans or domestic animals.

File:Non invasive SeV imaging of variable murine strains.png of infection in the respiratory tracts of living mice]]

File:Electron microscopy of Sendai virus.png of virus]]

Inbred and outbred mouse and rat strains have very different susceptibility to Sendai virus infection.{{cite journal | vauthors = Faisca P, Anh DB, Desmecht DJ | title = Sendai virus-induced alterations in lung structure/function correlate with viral loads and reveal a wide resistance/susceptibility spectrum among mouse strains | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 289 | issue = 5 | pages = L777–L787 | date = November 2005 | pmid = 16006482 | doi = 10.1152/ajplung.00240.2005 }} Visualization of SeV infection in live animals demonstrates this difference.{{cite journal |vauthors=Burke CW, Mason JN, Surman SL, Jones BG, Dalloneau E, Hurwitz JL, Russell CJ |date=July 2011 |title=Illumination of parainfluenza virus infection and transmission in living animals reveals a tissue-specific dichotomy |journal=PLOS Pathogens |volume=7 |issue=7 |pages=e1002134 |doi=10.1371/journal.ppat.1002134 |pmc=3131265 |pmid=21750677 |doi-access=free}} The 129/J mice tested were approximately 25,000-fold more sensitive than SJL/J mice.{{cite journal |vauthors=Parker JC, Whiteman MD, Richter CB |title=Susceptibility of inbred and outbred mouse strains to Sendai virus and prevalence of infection in laboratory rodents |journal=Infection and Immunity|volume=19 |issue=1 |pages=123–30 |date=January 1978 |pmid=203530 |pmc=414057 |doi=10.1128/IAI.19.1.123-130.1978}} C57BL/6 mice are highly resistant to the virus, while DBA/2J mice are sensitive.{{cite journal |vauthors=Brownstein DG, Winkler S |title=Genetic resistance to lethal Sendai virus pneumonia: virus replication and interferon production in C57BL/6J and DBA/2J mice |journal=Laboratory Animal Science|volume=36 |issue=2 |pages=126–9 |date=April 1986 |pmid=2422437}} C57BL/6 mice showed slight loss of body weight after SeV administration, which returned to normal later. Only 10% mortality rate was observed in C57BL/6 mice after the administration of very high virulent dose of 1*10⁵ TCID50.{{cite journal |vauthors=Simon AY, Moritoh K, Torigoe D, Asano A, Sasaki N, Agui T |title=Multigenic control of resistance to Sendai virus infection in mice |journal=Infection, Genetics and Evolution|volume=9 |issue=6 |pages=1253–9 |date=December 2009 |pmid=19733691 |doi=10.1016/j.meegid.2009.08.011 |bibcode=2009InfGE...9.1253S |hdl=2115/42554 | hdl-access = free}} It was shown that resistance to the lethal effects of Sendai virus in mice is genetically controlled and expressed through control of viral replication within the first 72 hours of infection. Treatment of both strains with exogenous IFN before and during viral infection led to an increase in survival time in C57BL/6 mice, but all animals of both strains ultimately succumb to SeV caused disease.{{cite journal |vauthors=Breider MA, Adams LG, Womack JE |title=Influence of interferon in natural resistance of mice to Sendai virus pneumonia |journal=American Journal of Veterinary Research|volume=48 |issue=12 |pages=1746–50 |date=December 1987 |pmid=2449103}} If a mouse survives a SeV infection, it develops a lifelong immunity to subsequent viral infections.{{cite journal |vauthors=Sangster M, Smith FS, Coleclough C, Hurwitz JL |title=Human parainfluenza virus type 1 immunization of infant mice protects from subsequent Sendai virus infection |journal=Virology|volume=212 |issue=1 |pages=13–9 |date=September 1995 |pmid=7676623 |doi=10.1006/viro.1995.1448|doi-access=free }}

There are SeV-resistant F344 rats and susceptible BN rats.{{cite journal |vauthors=Stone AE, Giguere S, Castleman WL |title=IL-12 reduces the severity of Sendai virus-induced bronchiolar inflammation and remodeling |journal=Cytokine|volume=24 |issue=3 |pages=103–13 |date=November 2003 |pmid=14581004 |doi=10.1016/j.cyto.2003.07.005}}

In the host airways the virus titer reaches a peak after 5–6 days post infection initiation that decreases to undetectable levels by day 14.{{cite web |title=Sendai Virus (SV) |url=http://ratguide.com/health/viruses/sendai_virus_sv.php |work=Rat Guide}} The virus promotes a descending respiratory infection, which begins in the nasal passages, passes through the trachea into the lungs and causes necrosis of the respiratory epithelium. The necrosis is mild in the first few days of infection, but later became severe by peaking around day 5. By day 9, the cells of the surface of the airways regenerate. Focal interstitial pneumonia can developed accompanied by inflammation and lesions of various degrees on the lungs. Usually, the respiratory system shows signs of healing within 3 weeks of infection, however, residual lesions, inflammation, or permanent scarring can occur. 6–8 days after the infection initiation serum antibodies appear. They remain detectable for about 1 year.

Source:

• Sneezing
• Hunched posture
• Respiratory distress
• Porphyrin discharge from eyes and/or nose
• Lethargy
• Failure to thrive in surviving babies and young rats
• Anorexia

SeV induces lesions within the respiratory tract, usually associated with bacterial inflammation of the trachea and lung (tracheitis and bronchopneumonia, respectively). However, the lesions are limited, and aren't indicative solely of SeV infection. Detection, therefore, makes use of SeV-specific antigens in several serological methods, including ELISA, immunofluorescence, and hemagglutination assays, with particular emphasis on use of the ELISA for its high sensitivity (unlike the hemagglutination assay) and its fairly early detection (unlike the immunofluorescence assay).{{cite journal |vauthors=Kraft V, Meyer B |title=Diagnosis of murine infections in relation to test methods employed |journal=Laboratory Animal Science|volume=36 |issue=3 |pages=271–6 |date=June 1986 |pmid=3014210}}

In a natural setting, the respiratory infection of Sendai virus in mice is acute. From the extrapolation of the infection of laboratory mice, the presence of the virus may first be detected in the lungs 48 to 72 hours following exposure. As the virus replicates in the respiratory tract of an infected mouse, the concentration of the virus grows most quickly during the third day of infection. After that, the growth of the virus is slower but consistent. Typically, the peak concentration of the virus is on the sixth or seventh day, and rapid decline follows that by the ninth day. A fairly vigorous immune response mounted against the virus is the cause of this decline. The longest period of detected presence of the virus in a mouse lung is fourteen days after infection.{{cite book | vauthors = Lock LF | chapter = Mouse and Human Pluripotent Stem Cells |title=The Mouse in Biomedical Research | edition = 2nd | veditors = Fox JG, Barthold S, Davisson M, Newcomer CE, Quimby FW, Smith A |publisher=Academic Press|year=2007 |location=Amsterdam |pages=281–309 |doi=10.1016/B978-012369454-6/50039-X}}

Eaton et al. advises that, when controlling an outbreak of SeV, disinfecting the laboratory environment and vaccinating the breeders, as well as eliminating infected animals and screening incoming animals, should clear the problem very quickly. Imported animals should be vaccinated with SeV and placed in quarantine, while, in the laboratory environment, breeding programs should be discontinued, and the non-breeding adults isolated for two months.{{cite journal |vauthors=Eaton GJ, Lerro A, Custer RP, Crane AR |title=Eradication of Sendai pneumonitis from a conventional mouse colony |journal=Laboratory Animal Science|volume=32 |issue=4 |pages=384–6 |date=August 1982 |pmid=6292576}}

The virus is a powerful immunomodulator. SeV can act in both directions: it can activate or suppress the immune response depending on the type of cell, host and time period after infection initiation. The virus can suppress the IFN production and response pathways as well as inflammation pathway.{{cite journal | vauthors = Popli S, Chakravarty S, Fan S, Glanz A, Aras S, Nagy LE, Sen GC, Chakravarti R, Chattopadhyay S | title = IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 119 | issue = 37 | pages = e2121385119 | date = September 2022 | pmid = 36067309 | doi = 10.1073/pnas.2121385119 | bibcode = 2022PNAS..11921385P | doi-access = free | pmc = 9478676 }}

Sendai virus P gene encodes a nested set of proteins (C', C, Y1 and Y2), which are named to collectively as the C proteins (see the section "genome structure" below). C proteins of SeV are able to suppress apoptosis.{{cite journal |vauthors=Koyama AH, Irie H, Kato A, Nagai Y, Adachi A |title=Virus multiplication and induction of apoptosis by Sendai virus: role of the C proteins |journal=Microbes and Infection|volume=5 |issue=5 |pages=373–8 |date=April 2003 |pmid=12737992 |doi=10.1016/S1286-4579(03)00043-1|doi-access=free }} The antiapoptotic activity of the C proteins supports SeV infection in the host cells.

The virus prevents the stimulation of type 1 IFN production and subsequent cell apoptosis in response to virus infection by inhibiting the activation of IRF-3.{{cite journal |vauthors=Kiyotani K, Sakaguchi T, Kato A, Nagai Y, Yoshida T |title=Paramyxovirus Sendai virus V protein counteracts innate virus clearance through IRF-3 activation, but not via interferon, in mice |journal=Virology|volume=359 |issue=1 |pages=82–91 |date=March 2007 |pmid=17027894 |doi=10.1016/j.virol.2006.08.053|doi-access=free }}{{cite journal |vauthors=Irie T, Nagata N, Igarashi T, Okamoto I, Sakaguchi T |title=Conserved charged amino acids within Sendai virus C protein play multiple roles in the evasion of innate immune responses |journal=PLOS ONE|volume=5 |issue=5 |pages=e10719 |date=May 2010 |pmid=20502666 |pmc=2873429 |doi=10.1371/journal.pone.0010719 |bibcode=2010PLoSO...510719I|doi-access=free }}{{cite journal |vauthors=Kato A, Ohnishi Y, Kohase M, Saito S, Tashiro M, Nagai Y |title=Y2, the smallest of the Sendai virus C proteins, is fully capable of both counteracting the antiviral action of interferons and inhibiting viral RNA synthesis |journal=Journal of Virology|volume=75 |issue=8 |pages=3802–10 |date=April 2001 |pmid=11264369 |pmc=114871 |doi=10.1128/JVI.75.8.3802-3810.2001}} Two virus proteins: C and V are mainly involved in this process. SeV can attenuate cell defense mechanisms and allow itself to escape from host innate immunity by inhibiting the interferon response pathway in addition to inhibiting the interferon production. The table below demonstrates the inhibition mechanism.

Anti-IFN activity of C protein is shared across the family Paramyxoviridae, and therefore appears to play an important role in paramyxovirus immune evasion. Human Parainfluenza Virus type 1 (HPIV1), which is a close relative of SeV and is (in contrast to SeV) a successful human pathogen, does not express V proteins, only C proteins. So, all needed functions provided by V in SeV can be provided by C in HPIV1. Thus, C and V have these "overlapping functions" because of the multi-faceted nature of host defense that can be countered at so many places, and exactly how well and where will in part explain host restriction.{{cite journal |vauthors=Rochat S, Komada H, Kolakofsky D |title=Loss of V protein expression in human parainfluenza virus type 1 is not a recent event |journal=Virus Research|volume=24 |issue=2 |pages=137–44 |date=July 1992 |pmid=1326826 |doi=10.1016/0168-1702(92)90002-q}}

The C-protein also appears to be responsible for limiting the production of NO in infected macrophages, which in turn reduces inflammation. {{cite journal | vauthors = Odkhuu E, Komatsu T, Koide N, Naiki Y, Takeuchi K, Tanaka Y, Tsolmongyn B, Jambalganiin U, Morita N, Yoshida T, Gotoh B, Yokochi T | title = Sendai virus C protein limits NO production in infected RAW264.7 macrophages | journal = Innate Immunity | volume = 24 | issue = 7 | pages = 430–438 | date = October 2018 | pmid = 30189760 | pmc = 6830875 | doi = 10.1177/1753425918796619 }}

Currently, there is no scientific data obtained using modern detection methods that would identify SeV as an infectious - disease causing agent for humans or domestic animals. Modern methods for the identification of pathogenic microorganisms have never detected SeV in pigs or other domestic animals, despite the isolation of other paramyxoviruses.{{cite journal |vauthors=Qiao D, Janke BH, Elankumaran S |date=August 2009 |title=Molecular characterization of glycoprotein genes and phylogenetic analysis of two swine paramyxoviruses isolated from United States |journal=Virus Genes |volume=39 |issue=1 |pages=53–65 |doi=10.1007/s11262-009-0353-2 |pmid=19337823 |s2cid=7100230}}{{cite journal |vauthors=Qiao D, Janke BH, Elankumaran S |date=January 2010 |title=Complete genome sequence and pathogenicity of two swine parainfluenzavirus 3 isolates from pigs in the United States |journal=Journal of Virology |volume=84 |issue=2 |pages=686–94 |doi=10.1128/JVI.00847-09 |pmc=2798373 |pmid=19906928}} Consequently, it is recognized that Sendai virus disease causing infection is host restrictive for rodents and the virus does not cause disease in humans or domestic animals, which are natural hosts for their own parainfluenza viruses. After experimental SeV infection the virus can replicate and shed from the upper and lower respiratory tract of African green monkeys and chimpanzees, but it is not causing any disease.{{cite journal |vauthors=Skiadopoulos MH, Surman SR, Riggs JM, Elkins WR, St Claire M, Nishio M, Garcin D, Kolakofsky D, Collins PL, Murphy BR |title=Sendai virus, a murine parainfluenza virus type 1, replicates to a level similar to human PIV1 in the upper and lower respiratory tract of African green monkeys and chimpanzees |journal=Virology|volume=297 |issue=1 |pages=153–60 |date=May 2002 |pmid=12083845 |doi=10.1006/viro.2002.1416 |url=http://archive-ouverte.unige.ch/unige:38133|doi-access=free }} Sendai virus has been used and demonstrated high safety profile in clinical trials involving both adults and children to immunize against human parainfluenza virus type 1, since the two viruses share common antigenic determinants and trigger the generation of cross-reactive neutralizing antibodies. The study that was published in 2011 demonstrated that SeV neutralizing antibodies (which were formed due to human parainfluenza virus type 1 past infection) can be detected in 92.5% of human subjects worldwide with a median EC₅₀ titer of 60.6 and values ranging from 5.9 to 11,324. Low anti-SeV antibodies background does not block the ability of SeV-base vaccine to promote antigen-specific T cell immunity.{{cite journal |vauthors=Moriya C, Horiba S, Inoue M, Iida A, Hara H, Shu T, Hasegawa M, Matano T |title=Antigen-specific T-cell induction by vaccination with a recombinant Sendai virus vector even in the presence of vector-specific neutralizing antibodies in rhesus macaques |journal=Biochemical and Biophysical Research Communications|volume=371 |issue=4 |pages=850–4 |date=July 2008 |pmid=18466766 |doi=10.1016/j.bbrc.2008.04.156}}

In 1952, Kuroya and his colleagues attempted to identify an infectious agent in human tissue samples at Tohoku University Hospital, Sendai, Japan. The samples were taken from the lung of a newborn child that was affected by fatal pneumonia. The primary isolate from the samples was passaged in mice and subsequently in embryonated eggs.{{cite journal |vauthors=Kuroya M, Ishida N |title=Newborn virus pneumonitis (type Sendai). II. The isolation of a new virus possessing hemagglutinin activity |journal=Yokohama Medical Bulletin|volume=4 |issue=4 |pages=217–33 |date=August 1953 |pmid=13137076}}{{cite journal |vauthors=Kuroya M, Ishida N, Shiratori T |title=Newborn virus pneumonitis (type Sendai). II. The isolation of a new virus |journal=The Tohoku Journal of Experimental Medicine|volume=58 |issue=1 |pages=62 |date=June 1953 |pmid=13102529 |doi=10.1620/tjem.58.62 | doi-access = free}} The isolated infectious agent was later called Sendai virus, which was used interchangeably with the name “Hemagglutinating Virus of Japan”. Kuroya and his colleagues were convinced that they isolated the virus, which is a new etiological agent for human respiratory infections. Later in 1954, Fukumi and his colleagues at the Japan National Institute of Health put forward an alternative explanation for the origin of the virus. It was suggested that the mice used to passage the virus were infected with the mouse virus. Thus, mouse virus was later transferred to embryonated eggs, isolated and finally named the Sendai virus.{{cite journal |vauthors=Fukumi H, Nishikawa F, Kitayama T |title=A pneumotropic virus from mice causing hemagglutination |journal=Japanese Journal of Medical Science & Biology|volume=7 |issue=4 |pages=345–63 |date=August 1954 |pmid=13232830 |doi=10.7883/yoken1952.7.345 | doi-access = free}} This explanation of Fukumi, pointing to the mouse rather than the human origin of the virus, has been supported by numerous scientific data later. The historical aspects of the Sendai virus isolation and controversy behind it are well described in the review. Thus, for some time, it was erroneously assumed that Sendai virus is human disease causing pathogen.{{cite journal |vauthors=Ishida N, Homma M |title=Sendai virus |journal=Advances in Virus Research|volume=23 |pages=349–83 |date=1978 |pmid=219669 |doi=10.1016/S0065-3527(08)60103-7 |isbn=9780120398232}} The incorrect assumption that the virus was isolated from human infectious material is still reported by Encyclopædia Britannica{{Cite encyclopedia |url=https://www.britannica.com/science/Sendai-virus |title=Sendai virus {{!}} infectious agent|encyclopedia=Encyclopedia Britannica|language=en |access-date=2019-08-26}} and by ATCC in the description of the history of the viral isolate Sendai/52.{{cite web |title=Sendai virus (ATCC VR-105) |url=https://www.atcc.org/products/all/VR-105.aspx#historySendai |work=American Type Culture Collection (ATCC)}} It was also believed that the virus could cause disease not only in humans but also in pigs, because antibodies to the virus were often found in their organisms during the swine epidemic in Japan in 1953–1956. High incidence of seropositivity to the virus was observed in pigs in 15 districts of Japan. An explanation was later found for this widespread detection of antibodies (see the section below). Yet, despite overwhelming evidence that indicate that SeV is host restrictive rodent pathogen, in some veterinary manuals.{{cite web | title = Sendai virus | work =Swine Health Information Center |publisher = Iowa State University, Center for Food Security and Public Health, College of Veterinary Medicine| date = September 2015 | url = http://www.cfsph.iastate.edu/pdf/shic-factsheet-sendai-virus }} and safety leaflets,{{cite web | url = https://ehs.stanford.edu/reference/sendai-virus-fact-sheet | title = Sendai Virus Fact Sheet | work =Stanford Environmental Health & Safety}}{{cite web | title = Recombinant Sendai Viral Vectors | url = https://d2vxd53ymoe6ju.cloudfront.net/wp-content/uploads/sites/4/20180824110855/Sendai-Viral-Vectors-Fact-Sheet.pdf | work = Occupational and Environmental Health and Safety | publisher = University of Utah }} SeV is still listed as a virus that can cause disease in pigs. Similar information is provided by Encyclopædia Britannica. In reality, the multiple isolates of paramyxoviruses in pigs, using modern nucleic acid sequencing methods, have never been identified as SeV.

All viruses in the family Paramyxoviridae are antigenically stable; therefore the family representatives that are close relatives and belong to the same genus, most likely, share common antigenic determinants. Thus, porcine parainfluenza 1,{{cite journal |vauthors=Lau SK, Woo PC, Wu Y, Wong AY, Wong BH, Lau CC, Fan RY, Cai JP, Tsoi HW, Chan KH, Yuen KY |title=Identification and characterization of a novel paramyxovirus, porcine parainfluenza virus 1, from deceased pigs |journal=The Journal of General Virology |volume=94 |issue=Pt 10 |pages=2184–90 |date=October 2013 |pmid=23918408 |doi=10.1099/vir.0.052985-0 | doi-access = free}}{{cite journal |vauthors=Palinski RM, Chen Z, Henningson JN, Lang Y, Rowland RR, Fang Y, Prickett J, Gauger PC, Hause BM |title=Widespread detection and characterization of porcine parainfluenza virus 1 in pigs in the USA |journal=The Journal of General Virology |volume=97 |issue=2 |pages=281–286 |date=February 2016 |pmid=26581410 |doi=10.1099/jgv.0.000343 | doi-access = free}} which has high sequence homology with SeV and also belongs to the same genus Respirovirus as SeV, probably, has cross-reactive antibodies with SeV. Perhaps the porcine parainfluenza 1 was responsible for pigs disease in Japan in 1953–1956. However, the antigenic cross-reactivity among these two representatives within the genus Respirovirus may explain why SeV antibodies were found in sick pigs, and why it was thought that SeV was the etiological causative agent of pigs disease. Human parainfluenza virus type 1, also shares common antigenic determinants with SeV and triggers the generation of cross-reactive neutralizing antibodies. This fact can explain wide spread detection of SeV antibodies in humans in the 1950s-1960s. Recently published study also showed this wide spread detection. The study that was published in 2011 demonstrated that SeV neutralizing antibodies (which were formed due to human parainfluenza virus type 1 past infection) can be detected in 92.5% of human subjects worldwide with a median EC₅₀ titer of 60.6 and values ranging from 5.9 to 11,324.{{cite journal |vauthors=Hara H, Hara H, Hironaka T, Inoue M, Iida A, Shu T, Hasegawa M, Nagai Y, Falsey AR, Kamali A, Anzala O, Sanders EJ, Karita E, Mwananyanda L, Vasan S, Lombardo A, Parks CL, Sayeed E, Krebs M, Cormier E, Ackland J, Price MA, Excler JL |title=Prevalence of specific neutralizing antibodies against Sendai virus in populations from different geographic areas: implications for AIDS vaccine development using Sendai virus vectors |journal=Human Vaccines |volume=7 |issue=6 |pages=639–45 |date=June 2011 |pmid=21508675 |doi=10.4161/hv.7.6.15408 |s2cid=24481304|doi-access=free }} Low anti-SeV antibodies background does not block the ability of SeV-base vaccine to promote antigen-specific T cell immunity.

Sendai virus administration to non-natural hosts results in shedding virions in the airways. Thus, 10 hours later after intranasal SeV administration, infectious virions carrying foreign trans genes can be detected in sheep's’ lungs.{{cite journal |vauthors=Griesenbach U, McLachlan G, Owaki T, Somerton L, Shu T, Baker A, Tennant P, Gordon C, Vrettou C, Baker E, Collie DD, Hasegawa M, Alton EW |title=Validation of recombinant Sendai virus in a non-natural host model |journal=Gene Therapy |volume=18 |issue=2 |pages=182–8 |date=February 2011 |pmid=20962870 |doi=10.1038/gt.2010.131 |s2cid=23293412 | doi-access = free}} Moreover, SeV replicates to detectable levels in the upper and lower respiratory tract of African green monkeys and chimpanzees.

SeV can overcome antiviral mechanisms in some of its natural hosts (some rodents), but the virus is ineffective in overcoming these mechanisms in some other organisms that are virus resistant.{{cite journal |vauthors=Bousse T, Chambers RL, Scroggs RA, Portner A, Takimoto T |title=Human parainfluenza virus type 1 but not Sendai virus replicates in human respiratory cells despite IFN treatment |journal=Virus Research |volume=121 |issue=1 |pages=23–32 |date=October 2006 |pmid=16677733 |doi=10.1016/j.virusres.2006.03.012}} Both innate and adaptive immunity promote efficient recovery from SeV infection.

The main component of innate antiviral response is type I interferons (IFNs) production and most cells can produce type I IFNs, including IFN-α and -β.{{cite journal |vauthors=Heylbroeck C, Balachandran S, Servant MJ, DeLuca C, Barber GN, Lin R, Hiscott J |title=The IRF-3 transcription factor mediates Sendai virus-induced apoptosis |journal=Journal of Virology |volume=74 |issue=8 |pages=3781–92 |date=April 2000 |pmid=10729153 |pmc=111887 |doi=10.1128/jvi.74.8.3781-3792.2000}} The recognition by cellular molecules that are called pattern recognition receptors (PRR) of triggering viral elements, such as the virus genomic RNA, the replication intermediary double-stranded RNA, or the viral ribonucleoproteins, promotes IFN production and response pathways. Viral genomic and protein components can bind variable PRRs and stimulate a signaling pathway that results in the activation of the transcription factors, which relocate to nucleus and trigger type I IFNs transcription.

File:Simon (RIG-I and Mda5).jpg

Because of powerful interferon stimulating properties, before recombinant interferon alpha became available for medical use, SeV was selected, among other viruses, for the industrial large-scale IFN production. A procedure involving inactivated SeV treatment of human peripheral blood leukocytes from donors’ blood was used for this production.{{cite book |vauthors=Cantell K, Hirvonen S, Kauppinen HL, Myllylä G |title=Production of interferon in human leukocytes from normal donors with the use of Sendai virus |chapter=[4] Production of interferon in human leukocytes from normal donors with the use of Sendai virus |series=Methods in Enzymology |volume=78 |issue=Pt A |pages=29–38 |date=1981 |pmid=6173603 |doi=10.1016/0076-6879(81)78094-7 |isbn=9780121819781}}

Below is a table that listed known PRRs and interferon regulatory factors that are getting activated upon SeV infection.

SeV can stimulate and/or inhibit the IFN-beta response pathway depending on the type of cell and host. If SeV triggers IFN production, the produced IFN further protects cells from next rounds of SeV infection. Multiple examples of IFN-beta protecting cells from SeV are described. Pretreatment of human lung fibroblasts MRC-5 cells with IFN-beta inhibits the replication of SeV.

A similar IFN-beta protection against the virus has been observed for some human malignant cells that maintain the IFN response pathway. HeLa cells can be infected with SeV; however, incubation of these cells with IFN-beta causes inhibition of SeV replication.{{cite journal |vauthors=Subramanian G, Kuzmanovic T, Zhang Y, Peter CB, Veleeparambil M, Chakravarti R, Sen GC, Chattopadhyay S |title=A new mechanism of interferon's antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene, TDRD7 |journal=PLOS Pathogens |volume=14 |issue=1 |pages=e1006877 |date=January 2018 |pmid=29381763 |pmc=5806901 |doi=10.1371/journal.ppat.1006877 | doi-access = free }} Multiple interferon stimulated genes (ISG) were identified as being required for this inhibition including IRF-9, TRIM69, NPIP, TDRD7, PNPT1 and so on. One of this genes TDRD7 was investigated in more detail. The functional TDRD7 protein inhibits the replication of SeV and other paramyxoviruses, suppressing autophagy, which is necessary for productive infection with these viruses.

SeV also triggers the expression of IFN induced Ifit2 protein that is involved in protecting mice from SeV through as yet unknown mechanism.{{cite journal |vauthors=Wetzel JL, Fensterl V, Sen GC |title=Sendai virus pathogenesis in mice is prevented by Ifit2 and exacerbated by interferon |journal=Journal of Virology |volume=88 |issue=23 |pages=13593–601 |date=December 2014 |pmid=25231314 |pmc=4248979 |doi=10.1128/JVI.02201-14}} In addition, SeV triggers the expression of the chemokine interferon-γ inducible protein 10 kDa (CXCL10), which is involved in chemotaxis, induction of apoptosis, regulation of cell growth and mediation of angiostatic effects. Human mast cell infection with SeV induces expression of interferon-stimulated genes MxA{{cite journal | vauthors = Haller O, Kochs G | title = Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity | journal = Journal of Interferon & Cytokine Research | volume = 31 | issue = 1 | pages = 79–87 | date = January 2011 | pmid = 21166595 | doi = 10.1089/jir.2010.0076 }} and IFIT3 in addition to activation of expression of type 1 IFN, MDA-5, RIG-1 and TLR-3.

Sendai virus can induce the production of many cytokines that enhance cellular immune responses. Some evidence that demonstrates that SeV activates the transcription factor NF-κB{{cite journal |vauthors=Peters K, Chattopadhyay S, Sen GC |title=IRF-3 activation by Sendai virus infection is required for cellular apoptosis and avoidance of persistence |journal=Journal of Virology |volume=82 |issue=7 |pages=3500–8 |date=April 2008 |pmid=18216110 |pmc=2268502 |doi=10.1128/JVI.02536-07}} and this activation helps in protection against SeV infection. SeV can stimulate the production of macrophage inflammatory protein-1α (MIB-1α) and –β (MIB-1β), RANTES (CCL5), tumor necrosis factor-alpha (TNF-alpha), tumor necrosis factor-beta (TNF-beta), interleukin-6 (IL-6 ), interleukin-8 (IL-8), interleukin-1 alpha (IL1A), interleukin-1 beta (IL1B), platelet-derived growth factor (PDGF-AB) and small concentrations of interleukin-2 (IL2) and GM-CSF. Sendai virus can trigger production of interleukin 12 (IL12) and interleukin 23 (IL23) in human macrophages.{{cite journal | vauthors = Pirhonen J, Matikainen S, Julkunen I | title = Regulation of virus-induced IL-12 and IL-23 expression in human macrophages | journal = Journal of Immunology | volume = 169 | issue = 10 | pages = 5673–5678 | date = November 2002 | pmid = 12421946 | doi = 10.4049/jimmunol.169.10.5673 }} Even plasmids that deliver the F-coding gene of SeV to tumor cells in model animals trigger the production of RANTES (CCL5) in tumor-infiltrated T-lymphocytes. SeV induces the production of B cell-activating factor by monocytes and by some other cells. Heat-inactivated SeV virus induces the production of IL-10 and IL-6 cytokines by dendritic cells (DC). Most likely, F protein is responsible for this induction because reconstituted liposomes containing F protein can stimulate IL-6 production by DC. The production of IL-6 in response to SeV infection is restricted to conventional dendritic cells (DCs]) subsets, such as CD4⁺ and double negative (dnDC).

The UV-inactivated SeV (and likely the alive virus as well) can stimulate dendritic cells to secrete chemokines and cytokines such as interleukin-6, interferon-beta, chemokine (C-C motif) ligand 5, and chemokine (C-X-C motif) ligand 10. These molecules activate both CD8⁺ T cells as well as natural killer cells. UV-inactivated SeV triggers the production of an intercellular adhesion molecule -1 (ICAM-1, CD54), which is a glycoprotein that serves as a ligand for macrophage-1 antigen (Mac-1) and lymphocyte function-associated antigen 1 (LFA-1 (integrin)). This induced production happens through the activation of NF-κB downstream of the mitochondrial antiviral signaling pathway and the RIG-I. The increased concentration of ICAM-1 on the cells surface increases the vulnerability of these cells to natural killer cells. It has been shown in the Namalwa cells that SeV virus stimulates an expression of many genes involved in immune defense pathways, such as type I and type II IFN signaling, as well as cytokine signaling. Among the ten most virus-induced mRNAs are IFNα8, IFNα13, IFNβ, IFNλ: (L28α, IL28β, IL29), OASL, CXCL10, CXCL11 and HERC5.

Using human embryonic kidney cells (HEK 293T) it has been shown that SeV can stimulate production of a pattern recognition receptor NLRC5, which is a cytosolic protein expressed mainly in hematopoietic cells.{{cite journal |vauthors=Neerincx A, Lautz K, Menning M, Kremmer E, Zigrino P, Hösel M, Büning H, Schwarzenbacher R, Kufer TA |title=A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses |journal=The Journal of Biological Chemistry |volume=285 |issue=34 |pages=26223–32 |date=August 2010 |pmid=20538593 |pmc=2924034 |doi=10.1074/jbc.M110.109736| doi-access = free }} This production activates the cryopyrin (NALP3) inflammasome.{{cite journal |vauthors=Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, Taraporewala ZF, Miller D, Patton JT, Inohara N, Núñez G |title=Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA |journal=The Journal of Biological Chemistry |volume=281 |issue=48 |pages=36560–8 |date=December 2006 |pmid=17008311 |doi=10.1074/jbc.M607594200 |s2cid=23488241 | doi-access = free}} Using human monocytic cell line-1 (THP-1) it has been shown that SeV can activate signal transduction by mitochondrial antiviral-signaling protein signaling (MAVS), which is a mitochondria-associated adaptor molecule that is required for optimal NALP3-inflammasome activity. Through MAVS signaling SeV stimulates the oligomerization of NALP3 and triggers NALP3-dependent activation of caspase-1{{cite journal |vauthors=Park S, Juliana C, Hong S, Datta P, Hwang I, Fernandes-Alnemri T, Yu JW, Alnemri ES |title=The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity |journal=Journal of Immunology |volume=191 |issue=8 |pages=4358–66 |date=October 2013 |pmid=24048902 |pmc=3848201 |doi=10.4049/jimmunol.1301170}} that, in turn, stimulates caspase 1-dependent production of interleukine -1 beta (IL-1β).{{cite journal |vauthors=Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN |title=The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation |journal=Cell |volume=153 |issue=2 |pages=348–61 |date=April 2013 |pmid=23582325 |pmc=3632354 |doi=10.1016/j.cell.2013.02.054}}

SeV is a very effective stimulant of expression of human beta-defensin-1 (hBD-1). This protein is a member of the beta-defensin family of proteins that bridges innate and adaptive immune responses to a pathogen infection.{{cite journal |vauthors=Ryan LK, Diamond G |title=Modulation of Human β-Defensin-1 Production by Viruses |journal=Viruses |volume=9 |issue=6 |pages=153 |date=June 2017 |pmid=28635669 |pmc=5490828 |doi=10.3390/v9060153 | doi-access = free}} In response to SeV infection, the production of hBD-1 mRNA and protein increases 2 hours after exposure to the virus in purified plasmacytoid dendritic cells or in PBMC.{{cite journal |vauthors=Ryan LK, Dai J, Yin Z, Megjugorac N, Uhlhorn V, Yim S, Schwartz KD, Abrahams JM, Diamond G, Fitzgerald-Bocarsly P |title=Modulation of human beta-defensin-1 (hBD-1) in plasmacytoid dendritic cells (PDC), monocytes, and epithelial cells by influenza virus, Herpes simplex virus, and Sendai virus and its possible role in innate immunity |journal=Journal of Leukocyte Biology |volume=90 |issue=2 |pages=343–56 |date=August 2011 |pmid=21551252 |pmc=3133436 |doi=10.1189/jlb.0209079}}

After viral infection in rodents, type I IFNs promote SeV clearance and speed up the migration and maturation of dendritic cells. However, soon after viral infection, animals efficiently generate cytotoxic T cells independently of type I IFN signaling and clear the virus from their lungs. Moreover, even the animals that are unresponsive to type I IFN develop long-term anti-SeV immunity in a form of memory response that includes generation of CD8⁺ T cells and neutralizing antibodies. This memory response can protect animals against further challenge with a lethal dose of virus.

SeV infection causes changes in a host cell protein phosphorylation, triggering phosphorylation of at least of 1347 host proteins.{{cite journal | vauthors = Öhman T, Söderholm S, Paidikondala M, Lietzén N, Matikainen S, Nyman TA | title = Phosphoproteome characterization reveals that Sendai virus infection activates mTOR signaling in human epithelial cells | journal = Proteomics | volume = 15 | issue = 12 | pages = 2087–2097 | date = June 2015 | pmid = 25764225 | doi = 10.1002/pmic.201400586 | s2cid = 32610482 }}

Sendai virus-based anticancer therapy for model{{cite journal |vauthors=Saga K, Kaneda Y |title=Oncolytic Sendai virus-based virotherapy for cancer: recent advances |journal=Oncolytic Virotherapy |volume=4 |pages=141–7 |date=2015 |pmid=27512677 |pmc=4918391 |doi=10.2147/OV.S66419 |doi-access=free }}{{cite journal |vauthors=Matveeva OV, Kochneva GV, Netesov SV, Onikienko SB, Chumakov PM |title=Mechanisms of Oncolysis by Paramyxovirus Sendai |journal=Acta Naturae |volume=7 |issue=2 |pages=6–16 |date=April 2015 |pmid=26085940 |pmc=4463408 |doi=10.32607/20758251-2015-7-2-6-16}} 50x50px Material was copied from this source, which is available under a Creative Commons Attribution License. and companion animals{{cite journal |vauthors=Ilyinskaya GV, Mukhina EV, Soboleva AV, Matveeva OV, Chumakov PM |title=Oncolytic Sendai Virus Therapy of Canine Mast Cell Tumors (A Pilot Study) |language=en |journal=Frontiers in Veterinary Science |volume=5 |pages=116 |date=2018 |pmid=29915788 |pmc=5995045 |doi=10.3389/fvets.2018.00116 | doi-access = free}} has been reported in several scientific papers. The described studies demonstrate that Sendai virus has a potential of becoming a safe and effective therapeutic agent against a wide range of human cancers. High genomic stability of SeV is a very desirable trait for oncolytic viruses. SeV is not likely to evolve into a pathogenic strain or into a virus with decreased oncolytic potential. The cytoplasmic replication of the virus results in a lack of host genome integration and recombination, which makes SeV safer and more attractive candidate for broadly used therapeutic oncolysis compared to some DNA viruses or retroviruses.

One of the great advantages of the Sendai virus as a potential oncolytic agent is its safety. Even though the virus is widespread in rodent colonies and has been used in laboratory research for decades,{{cite journal |vauthors=Nakanishi M, Otsu M |title=Development of Sendai virus vectors and their potential applications in gene therapy and regenerative medicine |journal=Current Gene Therapy |volume=12 |issue=5 |pages=410–6 |date=October 2012 |pmid=22920683 |pmc=3504922 |doi=10.2174/156652312802762518}} it has never been observed that it can cause human disease. Moreover, Sendai virus has been used in clinical trials involving both adults{{cite journal |vauthors=Slobod KS, Shenep JL, Luján-Zilbermann J, Allison K, Brown B, Scroggs RA, Portner A, Coleclough C, Hurwitz JL |title=Safety and immunogenicity of intranasal murine parainfluenza virus type 1 (Sendai virus) in healthy human adults |journal=Vaccine |volume=22 |issue=23–24 |pages=3182–6 |date=August 2004 |pmid=15297072 |doi=10.1016/j.vaccine.2004.01.053}} and children{{cite journal |vauthors=Adderson E, Branum K, Sealy RE, Jones BG, Surman SL, Penkert R, Freiden P, Slobod KS, Gaur AH, Hayden RT, Allison K, Howlett N, Utech J, Allay J, Knight J, Sleep S, Meagher MM, Russell CJ, Portner A, Hurwitz JL |title=Safety and immunogenicity of an intranasal Sendai virus-based human parainfluenza virus type 1 vaccine in 3- to 6-year-old children |journal=Clinical and Vaccine Immunology |volume=22 |issue=3 |pages=298–303 |date=March 2015 |pmid=25552633 |pmc=4340902 |doi=10.1128/CVI.00618-14}} to immunize against human parainfluenza virus type 1, since the two viruses share common antigenic determinants and trigger the generation of cross-reactive neutralizing antibodies. The Sendai virus administration in the form of nasal drops in doses ranging from 5 × 10⁵ 50% embryo infectious dose (EID50) to 5 × 10⁷ EID50 induced the production of neutralizing antibodies to the human virus without any measurable side effects.The results of these trials represent additional evidence of Sendai virus safety for humans. The development of T cell-based AIDS vaccines using Sendai virus vectors reached phase II clinical trial. Evaluation of the safety and immunogenicity of an intranasally administered replication-competent Sendai Virus–vectored HIV Type 1 gag vaccine demonstrated: induction of potent T-Cell and antibody responses in prime-boost regimens. Sendai virus also used as a backbone for vaccine against respiratory syncytial virus (RSV).{{cite journal | vauthors = Russell CJ, Hurwitz JL | title = Sendai Virus-Vectored Vaccines That Express Envelope Glycoproteins of Respiratory Viruses | journal = Viruses | volume = 13 | issue = 6 | date = May 2021 | page = 1023 | pmid = 34072332 | pmc = 8230104 | doi = 10.3390/v13061023 | doi-access = free }}

For cancer studies, it is desirable that the oncolytic virus be non-pathogenic for experimental animals, but the Sendai virus can cause rodent disease, which is a problem for research strategies. Two approaches have been used to overcome this problem and make Sendai virus non-pathogenic for mice and rats. One of these approaches included the creation of a set of genetically modified attenuated viral strains. Representatives of this set were tested on model animals carrying a wide range of transplantable human tumors. It has been shown that they can cause suppression or even eradication of fibrosarcoma,{{cite journal |vauthors=Kinoh H, Inoue M, Washizawa K, Yamamoto T, Fujikawa S, Tokusumi Y, Iida A, Nagai Y, Hasegawa M |title=Generation of a recombinant Sendai virus that is selectively activated and lyses human tumor cells expressing matrix metalloproteinases |journal=Gene Therapy |volume=11 |issue=14 |pages=1137–45 |date=July 2004 |pmid=15085175 |doi=10.1038/sj.gt.3302272 |s2cid=10376042 | doi-access = free}}{{cite journal |vauthors=Kinoh H, Inoue M |title=New cancer therapy using genetically-engineered oncolytic Sendai virus vector |journal=Frontiers in Bioscience |volume=13 |issue=13 |pages=2327–34 |date=January 2008 |pmid=17981715 |doi=10.2741/2847 |s2cid=25851804 |doi-access=free }} neuroblastoma,{{cite journal |vauthors=Tatsuta K, Tanaka S, Tajiri T, Shibata S, Komaru A, Ueda Y, Inoue M, Hasegawa M, Suita S, Sueishi K, Taguchi T, Yonemitsu Y |title=Complete elimination of established neuroblastoma by synergistic action of gamma-irradiation and DCs treated with rSeV expressing interferon-beta gene |journal=Gene Therapy |volume=16 |issue=2 |pages=240–51 |date=February 2009 |pmid=18987675 |doi=10.1038/gt.2008.161 |s2cid=27976395 | doi-access = free}} hepatocellular carcinoma,{{cite journal |vauthors=Zimmermann M, Armeanu-Ebinger S, Bossow S, Lampe J, Smirnow I, Schenk A, Lange S, Weiss TS, Neubert W, Lauer UM, Bitzer M |title=Attenuated and protease-profile modified sendai virus vectors as a new tool for virotherapy of solid tumors |journal=PLOS ONE |volume=9 |issue=3 |pages=e90508 |date=2014 |pmid=24598703 |pmc=3944018 |doi=10.1371/journal.pone.0090508 |bibcode=2014PLoSO...990508Z| doi-access = free }} melanoma, squamous cell{{cite journal |vauthors=Tanaka Y, Araki K, Tanaka S, Miyagawa Y, Suzuki H, Kamide D, Tomifuji M, Uno K, Harada E, Yamashita T, Ueda Y, Inoue M, Shiotani A |title=Oncolytic Sendai virus-induced tumor-specific immunoresponses suppress "simulated metastasis" of squamous cell carcinoma in an immunocompetent mouse model |journal=Head & Neck |volume=41 |issue=6 |pages=1676–1686 |date=June 2019 |pmid=30620422 |doi=10.1002/hed.25642 |s2cid=58561289}} and prostate carcinomas.{{cite journal |vauthors=Yonemitsu Y, Ueda Y, Kinoh H, Hasegawa M |title=Immunostimulatory virotherapy using recombinant Sendai virus as a new cancer therapeutic regimen |journal=Frontiers in Bioscience |volume=13 |issue=13 |pages=1892–8 |date=January 2008 |pmid=17981677 |doi=10.2741/2809|doi-access=free }} SeV construct suppresses micrometastasis of head and neck squamous cell carcinoma in an orthotopic nude mouse model.{{cite journal |vauthors=Tanaka Y, Araki K, Tanaka S, Miyagawa Y, Suzuki H, Kamide D, Tomifuji M, Uno K, Kimura E, Yamashita T, Ueda Y, Shiotani A |title=Sentinel Lymph Node-Targeted Therapy by Oncolytic Sendai Virus Suppresses Micrometastasis of Head and Neck Squamous Cell Carcinoma in an Orthotopic Nude Mouse Model |journal=Molecular Cancer Therapeutics |volume=18 |issue=8 |pages=1430–1438 |date=August 2019 |pmid=31171582 |doi=10.1158/1535-7163.MCT-18-1372 |s2cid=174812921 | doi-access = free}} Complete eradication of established gliosarcomas in immunocompetent rats has also been observed.{{cite journal |vauthors=Iwadate Y, Inoue M, Saegusa T, Tokusumi Y, Kinoh H, Hasegawa M, Tagawa M, Yamaura A, Shimada H |title=Recombinant Sendai virus vector induces complete remission of established brain tumors through efficient interleukin-2 gene transfer in vaccinated rats |journal=Clinical Cancer Research |volume=11 |issue=10 |pages=3821–7 |date=May 2005 |pmid=15897582 |doi=10.1158/1078-0432.CCR-04-1485 |s2cid=37657020 | doi-access = free}} SeV constructs have also been created with a modified protease cleavage site in the F-protein. The modification allowed the recombinant virus to specifically infect cancer cells that expressed the corresponding proteases.

[[File:Mast cell tumors treated with oncolytic Sendai virus .jpg|thumb|Canine mast cell tumors treated with oncolytic Sendai virus.

Case 1. Male dog of 7 years old developed cutaneous, ulcerated, and poorly differentiated mastocytoma (35 mm diameter) located close to his anus. (1) Primary tumor; (2) 2 weeks after the first virus treatment; (3) 4 weeks after the first virus treatment.

Case 2. Male German shorthaired pointer of 9 years old developed subcutaneous, regional (stage 2) intermediately differentiated mastocytoma. The primary tumor was removed without clean margins. (1) secondary growth 1 week after the surgical procedure; (2) 2 weeks after the first virus treatment; (3) 5 weeks after the first virus treatment.]]

Another approach of making Sendai virus non-pathogenic included the short-term treatment of the virions with ultraviolet light. Such treatment causes a loss of the virus replication ability. However, even this replication-deficient virus can induce the cancer cells death and stimulate anti-tumor immunity. It can trigger extensive apoptosis of human glioblastoma cells in culture, and it can efficiently suppress the growth of these cells in model animals.{{cite journal |vauthors=Tanaka M, Shimbo T, Kikuchi Y, Matsuda M, Kaneda Y |title=Sterile alpha motif containing domain 9 is involved in death signaling of malignant glioma treated with inactivated Sendai virus particle (HVJ-E) or type I interferon |journal=International Journal of Cancer |volume=126 |issue=8 |pages=1982–1991 |date=April 2010 |pmid=19830690 |doi=10.1002/ijc.24965 |s2cid=3414189 | doi-access = free}} The ultraviolet light treated virus can also kill human prostate cancer cells in culture{{cite journal |vauthors=Qian M, Tan HM, Yu N, Wang T, Zhang Q |title=Inactivated Sendai Virus Induces ROS-dependent Apoptosis and Autophagy in Human Prostate Cancer Cells |journal=Biomedical and Environmental Sciences |volume=31 |issue=4 |pages=280–289 |date=April 2018 |pmid=29773091 |doi=10.3967/bes2018.036|bibcode=2018BioES..31..280Q }} by triggering their apoptosis and eradicate tumors that originated from these cells in immunodeficient model animals.{{cite journal |vauthors=Kawaguchi Y, Miyamoto Y, Inoue T, Kaneda Y |title=Efficient eradication of hormone-resistant human prostate cancers by inactivated Sendai virus particle |journal=International Journal of Cancer |volume=124 |issue=10 |pages=2478–87 |date=May 2009 |pmid=19173282 |doi=10.1002/ijc.24234 |s2cid=33289879 | doi-access = free}} Moreover, it can stimulate immunomodulated tumor regression of colon{{cite journal |vauthors=Kurooka M, Kaneda Y |title=Inactivated Sendai virus particles eradicate tumors by inducing immune responses through blocking regulatory T cells |journal=Cancer Research |volume=67 |issue=1 |pages=227–36 |date=January 2007 |pmid=17210703 |doi=10.1158/0008-5472.CAN-06-1615 | doi-access = free}} and kidney cancers{{cite journal |vauthors=Nishikawa T, Tung LY, Kaneda Y |title=Systemic administration of platelets incorporating inactivated Sendai virus eradicates melanoma in mice |journal=Molecular Therapy |volume=22 |issue=12 |pages=2046–55 |date=December 2014 |pmid=25023327 |pmc=4429689 |doi=10.1038/mt.2014.128}} in immunocompetent mice. Similar regressions caused by the replication-deficient Sendai virus have been observed in animals with transplanted melanoma tumors.{{cite journal |vauthors=Zhang Q, Yuan WF, Zhai GQ, Zhu SY, Xue ZF, Zhu HF, Xu XM |title=Inactivated Sendai virus suppresses murine melanoma growth by inducing host immune responses and down-regulating β-catenin expression |journal=Biomedical and Environmental Sciences |volume=25 |issue=5 |pages=509–16 |date=October 2012 |pmid=23122307 |doi=10.3967/0895-3988.2012.05.003|bibcode=2012BioES..25..509Z }}{{cite journal |vauthors=Saga K, Tamai K, Yamazaki T, Kaneda Y |title=Systemic administration of a novel immune-stimulatory pseudovirion suppresses lung metastatic melanoma by regionally enhancing IFN-γ production |journal=Clinical Cancer Research |volume=19 |issue=3 |pages=668–79 |date=February 2013 |pmid=23251005 |doi=10.1158/1078-0432.CCR-12-1947 |s2cid=14105282 | doi-access = free}}

Some cancer studies with non-rodent animals have been performed with the unmodified Sendai virus. Thus, after intratumoral injections of the virus, complete or partial remission of mast cell tumors (mastocytomas) was observed in dogs affected by this disease. Short-term remission after an intravenous injection of SeV was described in a patient with acute leukemia treated in the Clinical Research Center of University Hospitals of Cleveland (USA) by multiple viruses in 1964.{{cite journal |vauthors=Wheelock EF, Dingle JH |title=Observations on the Repeated Administration of Viruses to a Patient With Acute Leukemia. A Preliminary Report |journal=The New England Journal of Medicine |volume=271 |issue=13 |pages=645–51 |date=September 1964 |pmid=14170843 |doi=10.1056/NEJM196409242711302}} It is also reported{{cite journal |vauthors=Zainutdinov SS, Kochneva GV, Netesov SV, Chumakov PM, Matveeva OV |title=Directed evolution as a tool for the selection of oncolytic RNA viruses with desired phenotypes |journal=Oncolytic Virotherapy |volume=8 |pages=9–26 |date=July 2019 |pmid=31372363 |pmc=6636189 |doi=10.2147/ov.s176523 |doi-access=free }} that the Moscow strain of SeV{{cite journal |vauthors=Zainutdinov SS, Tikunov AY, Matveeva OV, Netesov SV, Kochneva GV |title=Complete Genome Sequence of the Oncolytic Sendai virus Strain Moscow |journal=Genome Announcements |volume=4 |issue=4 |date=August 2016 |pmid=27516510 |pmc=4982289 |doi=10.1128/genomeA.00818-16}} was tested by Dr. V. Senin{{Citation |title=Treatment of advanced metastatic cancers with oncolytic Sendai virus | date=20 April 2014 |url=https://www.youtube.com/watch?v=xZQdpeoK3hc |archive-url=https://ghostarchive.org/varchive/youtube/20211219/xZQdpeoK3hc |archive-date=2021-12-19 |url-status=live|access-date=2019-08-21}}{{cbignore}} and his team as an anticancer agent in a few dozen patients affected by various malignancies with metastatic growth in Russia in the 1990s.{{Cite patent | country = US | number = 9526779 |title=Method for cancer immunotherapy and pharmaceutical compositions based on oncolytic non-pathogenic Sendai virus |url=https://patents.google.com/patent/US9526779B2/en | inventor = Matveeva O, Senina A, Slav V, Senin M | assign = Sendai Viralytics LLC | gdate = 27 December 2016 }} The virus was injected intradermally or intratumorally and it caused fever in less than half of the treated patients, which usually disappeared within 24 hours. Occasionally, the virus administration caused inflammation of the primary tumor and metastases. Clinical outcomes were variable. A small proportion of treated patients experienced pronounced long-term remission with the disappearance of primary tumors and metastases. Sometimes the remission lasted 5–10 years or more after virotherapy. Brief descriptions of the medical records of the patients that experiences long-term remission are presented in the patent. Intratumoral injection of UV irradiated and inactivated SeV resulted in an antitumor effect in a few melanoma patients with stage IIIC or IV progressive disease with skin or lymph metastasis. Complete or partial responses were observed in approximately half of injected and noninjected target lesions.{{cite journal |vauthors=Kiyohara E, Tanemura A, Nishioka M, Yamada M, Tanaka A, Yokomi A, Saito A, Sakura K, Nakajima T, Myoui A, Sakurai T, Kawakami Y, Kaneda Y, Katayama I |title=Intratumoral injection of hemagglutinating virus of Japan-envelope vector yielded an antitumor effect for advanced melanoma: a phase I/IIa clinical study |journal=Cancer Immunology, Immunotherapy |volume=69 |issue=6 |pages=1131–1140 |date=June 2020 |pmid=32047956 |doi=10.1007/s00262-020-02509-8 |s2cid=211074332|pmc=11027698 }}

Sendai virus can infect and kill variable cancer cells (see section Sensitive cell lines and virus strains). However, some malignant cells are resistant to SeV infection. There are multiple explanations for such resistance. Not all cancer cells have cell entry receptors for the virus and not all cancer cells express virus processing serine proteases. There are also other mechanisms that can make a cancer cell resistant to an oncolytic virus. For example, some cancer cells maintain interferon response system that completely or partially protects a host cells from a virus infection.{{cite journal | vauthors = Matveeva OV, Chumakov PM | title = Defects in interferon pathways as potential biomarkers of sensitivity to oncolytic viruses | journal = Reviews in Medical Virology | volume = 28 | issue = 6 | pages = e2008 | date = November 2018 | pmid = 30209859 | pmc = 6906582 | doi = 10.1002/rmv.2008 }} Therefore, biomarkers needed to be developed to identify tumors that might succumb to SeV mediated oncolysis.

SeV receptors are potential biomarkers for evaluation of the vulnerability of malignant cells to the virus. They represented by glycoproteins and glycolipids (see section "SeV cell entry receptors").The expression of some molecules that can facilitate SeV cell entry (see section “SeV cell entry receptors”), frequently, accelerates carcinogenesis and/or metastasis development. For example, the presence of Sialyl-Lewis^x antigen (cluster of differentiation 15s (CD15s)), which is one of SeV cell entry receptors, on the outer cell membrane, correlates with invasion potential of malignant cells, tumor recurrence, and overall patient survival for an extremely wide range of cancers.{{cite journal |vauthors=Liang JX, Liang Y, Gao W |title=Clinicopathological and prognostic significance of sialyl Lewis X overexpression in patients with cancer: a meta-analysis |journal=OncoTargets and Therapy |volume=9 |pages=3113–25 |date=May 2016 |pmid=27307752 |pmc=4888715 |doi=10.2147/ott.s102389 |doi-access=free }}{{cite journal |vauthors=Blanas A, Sahasrabudhe NM, Rodríguez E, van Kooyk Y, van Vliet SJ |title=Corrigendum: Fucosylated Antigens in Cancer: An Alliance Toward Tumor Progression, Metastasis, and Resistance to Chemotherapy |journal=Frontiers in Oncology |volume=8 |pages=150 |date=2018-05-11 |pmid=29795807 |pmc=5958677 |doi=10.3389/fonc.2018.00150 | doi-access = free}} Therefore, SeV virus preferentially can enter such cells.

Metastatic cancer cells frequently express a high density of glycoproteins or glycolipids - molecules that are rich in sialic acid.{{cite journal | vauthors = Fuster MM, Esko JD | title = The sweet and sour of cancer: glycans as novel therapeutic targets | journal = Nature Reviews. Cancer | volume = 5 | issue = 7 | pages = 526–542 | date = July 2005 | pmid = 16069816 | doi = 10.1038/nrc1649 | s2cid = 10330140 }} Expression of the Vim2 antigen, which is another SeV cell entry receptor, is very important for the extravascular infiltration process of acute myeloid leukemia cells.{{cite journal |vauthors=Noguchi M, Sato N, Sugimori H, Mori K, Oshimi K |title=A minor E-selectin ligand, CD65, is critical for extravascular infiltration of acute myeloid leukemia cells |journal=Leukemia Research |volume=25 |issue=10 |pages=847–53 |date=October 2001 |pmid=11532516 |doi=10.1016/s0145-2126(01)00036-4}} GD1a,{{Cite web |url=https://www.genome.jp/dbget-bin/www_bget?gl:G00111 |title=KEGG GLYCAN: G00111 |website=www.genome.jp |access-date=2019-08-13}} ganglioside also serves as SeV receptor and is found in large quantities on the surfaces of breast cancer stem cells.{{cite journal |vauthors=Liang YJ, Ding Y, Levery SB, Lobaton M, Handa K, Hakomori SI |title=Differential expression profiles of glycosphingolipids in human breast cancer stem cells vs. cancer non-stem cells |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=110 |issue=13 |pages=4968–73 |date=March 2013 |pmid=23479608 |pmc=3612608 |doi=10.1073/pnas.1302825110 |bibcode=2013PNAS..110.4968L|doi-access=free }} High cell surface expression of another SeV receptor - ganglioside sialosylparagloboside /SPG/ NeuAcα2-3PG.{{Cite web |url=https://chem.nlm.nih.gov/chemidplus/rn/71833-57-3 |title=ChemIDplus - 71833-57-3 - OWMXULOUTAAVIX-HNZIOFRCSA-N - Sialosylparagloboside - Similar structures search, synonyms, formulas, resource links, and other chemical information. | vauthors = Chambers M |website=chem.nlm.nih.gov |access-date=2019-08-13}} characterizes lymphoid leukemia cells.{{cite book |vauthors=Okegawa T |chapter=Detection of Circulating Tumor Cells in Castration-Resistant Prostate Cancer |title=Hormone Therapy and Castration Resistance of Prostate Cancer |date=2018 |pages=299–305 |publisher=Springer |location=Singapore |doi=10.1007/978-981-10-7013-6_30 |isbn=978-981-10-7012-9}}{{cite journal |vauthors=Hatano K, Miyamoto Y, Nonomura N, Kaneda Y |title=Expression of gangliosides, GD1a, and sialyl paragloboside is regulated by NF-κB-dependent transcriptional control of α2,3-sialyltransferase I, II, and VI in human castration-resistant prostate cancer cells |journal=International Journal of Cancer |volume=129 |issue=8 |pages=1838–47 |date=October 2011 |pmid=21165949 |doi=10.1002/ijc.25860 |s2cid=7765966 | doi-access = free}} Among other receptors represented by gangliosides GT1b is highly expressed on the outer membranes of brain metastases cells that originate from an extremely broad range of cancer,{{cite journal |vauthors=Hamasaki H, Aoyagi M, Kasama T, Handa S, Hirakawa K, Taki T |title=GT1b in human metastatic brain tumors: GT1b as a brain metastasis-associated ganglioside |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1437 |issue=1 |pages=93–9 |date=January 1999 |pmid=9931455 |doi=10.1016/s1388-1981(98)00003-1}} while GD1a, GT1b{{Cite web |url=https://www.genome.jp/dbget-bin/www_bget?gl:G00116 |title=KEGG GLYCAN: G00116 |website=www.genome.jp |access-date=2019-08-13}} and GQ1b{{Cite web |url=https://www.genome.jp/dbget-bin/www_bget?gl:G00117 |title=KEGG GLYCAN: G00117 |website=www.genome.jp |access-date=2019-08-13}} can be detected in human gliosarcomas. However, their quantity is not exceeding the quantity in normal frontal cerebral cortex.{{cite journal |vauthors=Vukelić Z, Kalanj-Bognar S, Froesch M, Bîndila L, Radić B, Allen M, Peter-Katalinić J, Zamfir AD |title=Human gliosarcoma-associated ganglioside composition is complex and distinctive as evidenced by high-performance mass spectrometric determination and structural characterization |journal=Glycobiology |volume=17 |issue=5 |pages=504–15 |date=May 2007 |pmid=17293353 |doi=10.1093/glycob/cwm012 | doi-access = free}} The asialoglycoprotein receptors that bind Sendai virus.{{cite journal |vauthors=Bitzer M, Lauer U, Baumann C, Spiegel M, Gregor M, Neubert WJ |title=Sendai virus efficiently infects cells via the asialoglycoprotein receptor and requires the presence of cleaved F0 precursor proteins for this alternative route of cell entry |journal=Journal of Virology |volume=71 |issue=7 |pages=5481–6 |date=July 1997 |pmid=9188621 |pmc=191789 |doi=10.1128/JVI.71.7.5481-5486.1997}} and serve as SeV cell entry receptors are highly expressed in liver cancers.{{Cite web |url=https://www.proteinatlas.org/ENSG00000141505-ASGR1 |title=ASGR1 protein expression summary - The Human Protein Atlas |website=www.proteinatlas.org |access-date=2020-01-14}}{{Cite web |url=https://www.proteinatlas.org/ENSG00000161944-ASGR2 |title=ASGR2 protein expression summary - The Human Protein Atlas |website=www.proteinatlas.org |access-date=2020-01-14}}

Cellular expression of glycoproteins can be evaluated by various molecular biology methods, which include RNA and protein measurements. However, cellular expression of gangliosides, which are sialic acid-containing glycosphingolipids, cannot be evaluated by these methods. Instead, it can be measured using anti-glycan antibodies, and despite the large collection of such antibodies in a community resource database, they are not always available for each ganglioside.{{cite journal |vauthors=Sterner E, Flanagan N, Gildersleeve JC |title=Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database |journal=ACS Chemical Biology |volume=11 |issue=7 |pages=1773–83 |date=July 2016 |pmid=27220698 |pmc=4949583 |doi=10.1021/acschembio.6b00244}} Therefore, indirect measurement of ganglioside expression by quantifying the levels of fucosyltransferases and glycosyltransferases that complete glycan synthesis is an alternative. There is evidence that expression of these enzymes and the production of gangliosides strongly correlate. At least four representatives of fucosyltransferases and several glycosyltransferases including sialyltransferases are responsible for the synthesis of gangliosides that can serve as SeV receptors. All these proteins are often overexpressed in various tumors, and their expression levels correlate with the metastatic status of the tumor and the shorter life span of the patients. Thus, these enzymes are also potential biomarkers of SeV-oncolytic infectivity

The fusion protein (F) of SeV is synthesized as an inactive precursor and is activated by proteolytic cleavage of the host cell serine proteases (see the section “Proteolytic cleavage by cellular proteases” below). Some of these proteases are overexpressed in malignant neoplasms. For example, transmembrane serine protease 2 (TMPRSS2), which is an F-protein-processing enzyme, is often overexpressed in prostate cancer cells.{{Cite web |url=https://www.proteinatlas.org/ENSG00000184012-TMPRSS2/pathology |title=Expression of TMPRSS2 in cancer - Summary - the Human Protein Atlas}} It is also overexpressed in some cell lines originating from various malignant neoplasms. Thus, it is highly expressed in bladder carcinoma,{{cite web |url=https://www.atcc.org/products/htb-2 |title=RT4 |publisher=ATCC |access-date=20 August 2021}} human colon carcinoma CaCo2{{cite journal |vauthors=Hidalgo IJ, Raub TJ, Borchardt RT |title=Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability |journal=Gastroenterology |volume=96 |issue=3 |pages=736–49 |date=March 1989 |pmid=2914637 |doi=10.1016/0016-5085(89)90897-4|doi-access=free }} and breast carcinomas SK-BR-3, MCF7 and [https://www.atcc.org/Products/All/HTB-133.aspx T-47d].{{Cite web |url=https://www.proteinatlas.org/ENSG00000184012-TMPRSS2/cell |title=Cell atlas - TMPRSS2 - The Human Protein Atlas |website=www.proteinatlas.org |access-date=2019-08-20}} TMPRSS2 is overexpressed in cervical and endocervical squamous cell carcinomas, along with colon, prostate, and rectum adenocarcinomas.{{cite journal | vauthors = Katopodis P, Anikin V, Randeva HS, Spandidos DA, Chatha K, Kyrou I, Karteris E | title = Pan‑cancer analysis of transmembrane protease serine 2 and cathepsin L that mediate cellular SARS‑CoV‑2 infection leading to COVID-19 | journal = International Journal of Oncology | volume = 57 | issue = 2 | pages = 533–539 | date = August 2020 | pmid = 32468052 | pmc = 7307597 | doi = 10.3892/ijo.2020.5071 }} It is also overexpressed in uterine corpus endometrial and uterine carcinosarcomas. Another F-protein-protease is tryptase beta 2 (TPSB2). This protease (with alias such as tryptase-Clara and mast cell tryptase) is expressed in normal club cells and mast cells, and in some cancers.{{Cite web |url=https://www.proteinatlas.org/ENSG00000197253-TPSB2/pathology |title=Expression of TPSB2 in cancer - Summary - The Human Protein Atlas |website=www.proteinatlas.org |access-date=2019-08-20}} It's especially high expression is observed in the human mast cell line HMC-1,{{Cite web |url=https://www.proteinatlas.org/ENSG00000197253-TPSB2/cell |title=Cell atlas - TPSB2 - The Human Protein Atlas |website=www.proteinatlas.org |access-date=2019-08-20}}{{cite journal |vauthors=Nilsson G, Blom T, Kusche-Gullberg M, Kjellén L, Butterfield JH, Sundström C, Nilsson K, Hellman L |title=Phenotypic characterization of the human mast-cell line HMC-1 |journal=Scandinavian Journal of Immunology |volume=39 |issue=5 |pages=489–98 |date=May 1994 |pmid=8191224 |doi=10.1111/j.1365-3083.1994.tb03404.x |s2cid=28014083}} and in the human erythroleukemia cell line HEL.{{cite journal |vauthors=Martin P, Papayannopoulou T |title=HEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression |journal=Science |volume=216 |issue=4551 |pages=1233–5 |date=June 1982 |pmid=6177045 |doi=10.1126/science.6177045 |bibcode=1982Sci...216.1233M}} The release of this tryptase from mast cells enhances tumor cell metastasis.{{cite journal | vauthors = Xiao H, He M, Xie G, Liu Y, Zhao Y, Ye X, Li X, Zhang M | title = The release of tryptase from mast cells promote tumor cell metastasis via exosomes | journal = BMC Cancer | volume = 19 | issue = 1 | pages = 1015 | date = October 2019 | pmid = 31664930 | pmc = 6819443 | doi = 10.1186/s12885-019-6203-2 | doi-access = free }} Plasminogen (PLG), from which originates the mini-plasmin that can cleave the F-protein, is highly expressed in liver cancers. Its expression is also increased in a wide range of other malignant neoplasms.{{Cite web |url=https://www.proteinatlas.org/ENSG00000122194-PLG/pathology |title=Expression of PLG in cancer - Summary - The Human Protein Atlas |website=www.proteinatlas.org |access-date=2019-08-20}} Factor X (F10) is frequently expressed in normal liver and in liver cancers.{{Cite web |url=https://www.proteinatlas.org/ENSG00000126218-F10/pathology |title=Expression of F10 in cancer - Summary - The Human Protein Atlas |website=www.proteinatlas.org |access-date=2019-08-30}} SeV constructs were created with a modified protease cleavage site. The modification allowed the recombinant virus to specifically infect cancer cells that expressed the corresponding proteases, which can cleave a modified protease cleavage site.

The interferon production and / or response system often malfunctions in malignant cells; therefore, they are much more vulnerable to infection with oncolytic viruses compared to normal cells Thus, cells belonging to three human cell lines, originated from variable malignancies, such as U937, [https://www.ncbi.nlm.nih.gov/pubmed/15894327 Namalwa], and A549, retain their ability to become infected with SeV even after treatment with type 1 IFN. Interferon response system is broken in these cells and it cannot protect them from SeV infection.{{cite journal |vauthors=Bedsaul JR, Zaritsky LA, Zoon KC |title=Type I Interferon-Mediated Induction of Antiviral Genes and Proteins Fails to Protect Cells from the Cytopathic Effects of Sendai Virus Infection |journal=Journal of Interferon & Cytokine Research |volume=36 |issue=11 |pages=652–665 |date=November 2016 |pmid=27508859 |pmc=5105340 |doi=10.1089/jir.2016.0051}}

In Namalwa cells SeV virus stimulates an expression of many genes involved in immune defense pathways, such as type I and type II IFN signaling, as well as cytokine signaling. Among the ten most virus-induced mRNAs are IFNα8, IFNα13, IFNβ, IFNλ: (L28α, IL28β, IL29), OASL, CXCL10, CXCL11 and HERC5.{{cite journal |vauthors=Mandhana R, Horvath CM |title=Sendai Virus Infection Induces Expression of Novel RNAs in Human Cells |journal=Scientific Reports |volume=8 |issue=1 |pages=16815 |date=November 2018 |pmid=30429577 |pmc=6235974 |doi=10.1038/s41598-018-35231-8 |bibcode=2018NatSR...816815M}} However, despite stimulation of these genes expression by SeV, Namalwa cells can't protect themselves from the virus infection.

In HeLa cells SeV (in contrast to Vesicular Stomatitis Virus) can counteract IFN-α pretreatment and keep a viral protein translation level similar to that in IFN-untreated cells.

It has been shown, using fibrosarcoma cell line L929, that SeV is able to induce malignant cell death through necroptosis. This type of cell death is highly immunogenic because dying necroptotic cells release damage-associated molecular pattern (DAMPs) molecules, which initiate adaptive immunity. The necroptotic pathway, triggered by SeV, requires RIG-I activation and the presence of SeV encoded proteins Y1 and/or Y2.{{cite journal |vauthors=Schock SN, Chandra NV, Sun Y, Irie T, Kitagawa Y, Gotoh B, Coscoy L, Winoto A |title=Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway |journal=Cell Death and Differentiation |volume=24 |issue=4 |pages=615–625 |date=April 2017 |pmid=28060376 |pmc=5384020 |doi=10.1038/cdd.2016.153}}

Viral neuraminidase has the ability to remove sialic acid residues from cell surfaces,{{Cite journal |last1=Goto |first1=Hideo |last2=Ohta |first2=Keisuke |last3=Matsumoto |first3=Yusuke |last4=Yumine |first4=Natsuko |last5=Nishio |first5=Machiko |date=September 2016 |editor-last=López |editor-first=S. |title=Evidence that Receptor Destruction by the Sendai Virus Hemagglutinin-Neuraminidase Protein Is Responsible for Homologous Interference |journal=Journal of Virology |language=en |volume=90 |issue=17 |pages=7640–7646 |doi=10.1128/JVI.01087-16 |issn=0022-538X |pmc=4988132 |pmid=27279623}} including those on T-regulatory (Treg) cells. Research indicates that the Sialyl-Lewis x antigen is specifically found in activated, terminally differentiated, and highly suppressive CD4+ regulatory T (Treg) cells, which can be distinguished from nonsuppressive T cell.{{Cite journal |last1=Miyara |first1=Makoto |last2=Chader |first2=Driss |last3=Sage |first3=Edouard |last4=Sugiyama |first4=Daisuke |last5=Nishikawa |first5=Hiroyoshi |last6=Bouvry |first6=Diane |last7=Claër |first7=Laetitia |last8=Hingorani |first8=Ravi |last9=Balderas |first9=Robert |last10=Rohrer |first10=Jurg |last11=Warner |first11=Noel |last12=Chapelier |first12=Alain |last13=Valeyre |first13=Dominique |last14=Kannagi |first14=Reiji |last15=Sakaguchi |first15=Shimon |date=2015-06-09 |title=Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3 high regulatory T cells in humans |journal=Proceedings of the National Academy of Sciences |language=en |volume=112 |issue=23 |pages=7225–7230 |doi=10.1073/pnas.1508224112 |doi-access=free |issn=0027-8424 |pmc=4466753 |pmid=26015572}}{{Cite journal |last1=Ohishi |first1=Kanae |last2=Ishikura |first2=Asaki |last3=Nishida |first3=Shogo |last4=Abo |first4=Hirohito |last5=Nakatsukasa |first5=Hiroko |last6=Kawashima |first6=Hiroto |date=2024-06-01 |title=Sialyl Lewis X Defines an Activated and Functional Regulatory T Cell Subpopulation in Mice |url=https://journals.aai.org/jimmunol/article/212/11/1627/266830/Sialyl-Lewis-X-Defines-an-Activated-and-Functional |journal=The Journal of Immunology |language=en |volume=212 |issue=11 |pages=1627–1638 |doi=10.4049/jimmunol.2300349 |pmid=38639586 |issn=0022-1767|url-access=subscription }} Removing the suppressive Treg cells from human blood has been shown to enhance immune responses against tumor and viral antigens in vitro. Removing the Sialyl-Lewis x antigen from Treg cells can inactivate their suppressive function.

The host organism fights viral infection using various strategies. One such strategy is the production of neutralizing antibodies. In response to this production, viruses have developed their own strategies for spreading the infection and avoiding the inactivation by the host produced neutralizing antibodies. Some viruses, and in particular paramyxoviruses, can produce new virus particles by fusing infected and healthy host cells. This fusion leads to the formation of a large multi-nuclear structure (syncytium). Sendai virus, as a representative of Paramyxoviridae, uses this strategy to spread its infection (see the section “Directed cell fusion” below). The virus can fuse up to 50-100 cells adjacent to one primary infected cell. This multi-nuclear formation, derived from several dozens of cells, survives for several days and subsequently releases functional viral particles.

It has been demonstrated that the ability of a virus to destroy tumor cells increases along with an increase in the ability of the virus to form large multi-nuclear structures. The transfer of genes that are responsible for the formation of syncytium from the representative of Paramyxoviridae to the representatives of Rhabdoviridae or Herpesviridae makes the recipient viruses more oncolytic.{{cite journal |vauthors=Ebert O, Shinozaki K, Kournioti C, Park MS, García-Sastre A, Woo SL |title=Syncytia induction enhances the oncolytic potential of vesicular stomatitis virus in virotherapy for cancer |journal=Cancer Research |volume=64 |issue=9 |pages=3265–70 |date=May 2004 |pmid=15126368 |doi=10.1158/0008-5472.CAN-03-3753 | doi-access = free}}{{cite journal |vauthors=Nakamori M, Fu X, Meng F, Jin A, Tao L, Bast RC, Zhang X |title=Effective therapy of metastatic ovarian cancer with an oncolytic herpes simplex virus incorporating two membrane fusion mechanisms |journal=Clinical Cancer Research |volume=9 |issue=7 |pages=2727–33 |date=July 2003 |pmid=12855653}} Moreover, the oncolytic potential of paramyxovirus can be enhanced by mutations in the fusion (F) gene protease-cleavage site, which allows the F-protein to be more efficiently processed by cellular proteases.{{cite journal |vauthors=Altomonte J, Marozin S, Schmid RM, Ebert O |title=Engineered newcastle disease virus as an improved oncolytic agent against hepatocellular carcinoma |journal=Molecular Therapy |volume=18 |issue=2 |pages=275–84 |date=February 2010 |pmid=19809404 |pmc=2839313 |doi=10.1038/mt.2009.231}} The introduction of the F gene of SeV in the form of a plasmid into the tumor tissue in mice by electroporation showed that the expression of the F gene increases the T cell infiltration of the tumor with CD4 + and CD8 + cells and inhibits tumor growth.{{cite journal |vauthors=Tai JA, Chang CY, Nishikawa T, Kaneda Y |title=Cancer immunotherapy using the Fusion gene of Sendai virus |journal=Cancer Gene Therapy |date=August 2019 |volume=27 |issue=6 |pages=498–508 |pmid=31383952 |doi=10.1038/s41417-019-0126-6 |s2cid=199450913 |url=https://ir.library.osaka-u.ac.jp/repo/ouka/all/76228/30871_Abstract.pdf }} It was also shown in other similar experiments that cancer cells themselves, transfected with plasmids that encode viral membrane glycoproteins with fusion function, cause the collective death of neighboring cells forming syncytium with them. Recruitment of bystander cells into the syncytium leads to significant regression of the tumor.{{cite journal |vauthors=Bateman A, Bullough F, Murphy S, Emiliusen L, Lavillette D, Cosset FL, Cattaneo R, Russell SJ, Vile RG |title=Fusogenic membrane glycoproteins as a novel class of genes for the local and immune-mediated control of tumor growth |journal=Cancer Research |volume=60 |issue=6 |pages=1492–7 |date=March 2000 |pmid=10749110}}{{cite journal |vauthors=Galanis E, Bateman A, Johnson K, Diaz RM, James CD, Vile R, Russell SJ |title=Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas |journal=Human Gene Therapy |volume=12 |issue=7 |pages=811–21 |date=May 2001 |pmid=11339897 |doi=10.1089/104303401750148766}}{{cite journal |vauthors=Lin EH, Salon C, Brambilla E, Lavillette D, Szecsi J, Cosset FL, Coll JL |title=Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer |journal=Cancer Gene Therapy |volume=17 |issue=4 |pages=256–65 |date=April 2010 |pmid=19893593 |doi=10.1038/cgt.2009.74 |s2cid=11203950 | doi-access = free}}

The virus triggers indirect immunomodulated death of malignant cells using a number of mechanisms, which are described in a published review. The viral enzyme neuraminidase (NA), which has sialidase activity, can make cancer cells more visible to the immune system by removing sialic acid residues from the surface of malignant cells. SeV activates natural killer cells (NK), cytotoxic T lymphocytes (CTL) and dendritic cells (DC). The secretion of interleukin-6, that is triggered by the virus, also inhibits regulatory T cells.

File:Intereferon and cancer cells.png functions of type I interferons]]

Type I and type II interferons have anticancer activity (see the "Function" section in the "Interferon" article). Interferons can promote expression of major histocompatibility complex molecules, MHC I and MHC II, and stimulate immunoproteasome activity. All interferons drastically increase the presentation of MHC I dependent antigens. Interferon gamma (IFN-gamma) also strongly promotes the MHC II-dependent presentation of antigens.{{cite journal |vauthors=Kursunel MA, Esendagli G |title=Corrigendum to "The untold story of IFN-γ in cancer biology" [Cytokine Growth Factor Rev. 31 (2016) 73-81] |journal=Cytokine & Growth Factor Reviews |volume=35 |pages=97 |date=June 2017 |pmid=28258821 |doi=10.1016/j.cytogfr.2017.02.002}} Higher MHC I expression leads to higher presentation of viral and abnormal peptides from cancer cells to cytotoxic T cells, while the immunoproteasome more efficiently processes these peptides for loading onto the MHC I molecule. Therefore, the recognition and killing of infected or malignant cells increases. Higher MHC II expression enhances presentation of viral and cancer peptides to helper T cells; which are releasing cytokines (such as more interferons, interleukins and other cytokines) that stimulate and co-ordinate the activity of other immune cells.{{cite journal |vauthors=Ikeda H, Old LJ, Schreiber RD |title=The roles of IFN gamma in protection against tumor development and cancer immunoediting |journal=Cytokine & Growth Factor Reviews |volume=13 |issue=2 |pages=95–109 |date=April 2002 |pmid=11900986 |doi=10.1016/s1359-6101(01)00038-7}}{{cite journal |vauthors=Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, Diamond MS, Koebel CM, Arthur C, White JM, Schreiber RD |title=A critical function for type I interferons in cancer immunoediting |journal=Nature Immunology |volume=6 |issue=7 |pages=722–9 |date=July 2005 |pmid=15951814 |doi=10.1038/ni1213 |s2cid=20374688 }}{{cite journal |vauthors=Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, Stark GR |title=Interferons at age 50: past, current and future impact on biomedicine |journal=Nature Reviews. Drug Discovery |volume=6 |issue=12 |pages=975–90 |date=December 2007 |pmid=18049472 |doi=10.1038/nrd2422 |pmc=7097588 |s2cid=583709}}

By down regulation of angiogenic stimuli produced by tumor cells interferon can also suppress angiogenesis{{cite journal |vauthors=Albini A, Marchisone C, Del Grosso F, Benelli R, Masiello L, Tacchetti C, Bono M, Ferrantini M, Rozera C, Truini M, Belardelli F, Santi L, Noonan DM |title=Inhibition of angiogenesis and vascular tumor growth by interferon-producing cells: A gene therapy approach |journal=The American Journal of Pathology |volume=156 |issue=4 |pages=1381–93 |date=April 2000 |pmid=10751362 |pmc=1876903 |doi=10.1016/S0002-9440(10)65007-9}} In addition, they suppress the proliferation of endothelial cells. Such suppression causes a decrease in tumor vascularization and subsequent growth inhibition. Interferons can directly activate immune cells including macrophages and natural killer cells. INF-1 and interferon gamma (IFN-γ) production are triggered by SeV molecular components in many cells (See "Virus induced antiviral immunity" section above).{{cite journal |vauthors=Hua J, Liao MJ, Rashidbaigi A |title=Cytokines induced by Sendai virus in human peripheral blood leukocytes |journal=Journal of Leukocyte Biology |volume=60 |issue=1 |pages=125–8 |date=July 1996 |pmid=8699116 |doi=10.1002/jlb.60.1.125 |s2cid=28976518}}{{cite journal |vauthors=Costas MA, Mella D, Criscuolo M, Díaz A, Finkielman S, Nahmod VE, Arzt E |title=Superinduction of mitogen-stimulated interferon-gamma production and other lymphokines by Sendai virus |journal=Journal of Interferon Research |volume=13 |issue=6 |pages=407–12 |date=December 1993 |pmid=8151134 |doi=10.1089/jir.1993.13.407}}{{cite journal |vauthors=Zidovec S, Mazuran R |title=Sendai virus induces various cytokines in human peripheral blood leukocytes: different susceptibility of cytokine molecules to low pH |journal=Cytokine |volume=11 |issue=2 |pages=140–3 |date=February 1999 |pmid=10089135 |doi=10.1006/cyto.1998.0411}}{{cite journal |vauthors=Lin HY, Davis PJ, Thacore HR |title=Production of human interferon-beta by Sendai virus and poly(rI).poly(rC): inhibition by neomycin |journal=Journal of Interferon Research |volume=11 |issue=6 |pages=365–9 |date=December 1991 |pmid=1666117 |doi=10.1089/jir.1991.11.365}} It has been demonstrated that SeV can also induce the production of IFN type III (IFN-lambda){{cite journal |vauthors=Donnelly RP, Kotenko SV |title=Interferon-lambda: a new addition to an old family |journal=Journal of Interferon & Cytokine Research |volume=30 |issue=8 |pages=555–64 |date=August 2010 |pmid=20712453 |pmc=2925029 |doi=10.1089/jir.2010.0078}} by human plasmacytoid dendritic cells.{{cite journal |vauthors=Yin Z, Dai J, Deng J, Sheikh F, Natalia M, Shih T, Lewis-Antes A, Amrute SB, Garrigues U, Doyle S, Donnelly RP, Kotenko SV, Fitzgerald-Bocarsly P |title=Type III IFNs are produced by and stimulate human plasmacytoid dendritic cells |journal=Journal of Immunology |volume=189 |issue=6 |pages=2735–45 |date=September 2012 |pmid=22891284 |pmc=3579503 |doi=10.4049/jimmunol.1102038}}

Sendai virus can induce the production of many cytokines that enhance cellular immune responses against cancer cells. SeV stimulates the production of macrophage inflammatory protein-1α (MIB-1α) and –β (MIB-1β), RANTES (CCL5), tumor necrosis factor-alpha (TNF-alpha), tumor necrosis factor-beta (TNF-beta), interleukin-6 (IL-6 ), interleukin-8 (IL-8), interleukin-1 alpha (IL1A), interleukin-1 beta (IL1B), platelet-derived growth factor (PDGF-AB) and small concentrations of interleukin-2 (IL2) and GM-CSF. The virus can trigger production of interleukin 12 (IL12) and interleukin 23 (IL23) in human macrophages. Even plasmids that deliver the F-coding gene of SeV to tumor cells in model animals trigger the production of RANTES (CCL5) in tumor-infiltrated T-lymphocytes.{{cite journal |vauthors=Suzuki H, Kurooka M, Hiroaki Y, Fujiyoshi Y, Kaneda Y |title=Sendai virus F glycoprotein induces IL-6 production in dendritic cells in a fusion-independent manner |journal=FEBS Letters |volume=582 |issue=9 |pages=1325–9 |date=April 2008 |pmid=18358837 |doi=10.1016/j.febslet.2008.03.011 |s2cid=207607018 | doi-access = free|bibcode=2008FEBSL.582.1325S }}

SeV induces the production of B cell-activating factor by monocytes and by some other cells.{{cite journal |vauthors=Ittah M, Miceli-Richard C, Lebon P, Pallier C, Lepajolec C, Mariette X |title=Induction of B cell-activating factor by viral infection is a general phenomenon, but the types of viruses and mechanisms depend on cell type |journal=Journal of Innate Immunity |volume=3 |issue=2 |pages=200–7 |date=2011 |pmid=21051868 |doi=10.1159/000321194 |s2cid=6699971 | doi-access = free}}

Heat-inactivated SeV virus induces the production of IL-10 and IL-6 cytokines by dendritic cells (DC).{{cite journal |vauthors=Johansson E, Domeika K, Berg M, Alm GV, Fossum C |title=Characterisation of porcine monocyte-derived dendritic cells according to their cytokine profile |journal=Veterinary Immunology and Immunopathology |volume=91 |issue=3–4 |pages=183–97 |date=February 2003 |pmid=12586481 |doi=10.1016/s0165-2427(02)00310-0}} Most likely, F protein is responsible for this induction because reconstituted liposomes containing F protein can stimulate IL-6 production by DC. The production of IL-6 in response to SeV infection is restricted to [https://www.nature.com/subjects/myeloid-dendritic-cells conventional dendritic cells (DCs]) subsets, such as CD4⁺ and double negative (dnDC).

The UV-inactivated SeV (and likely the alive virus as well) can stimulate dendritic cells to secrete chemokines and cytokines such as interleukin-6, interferon-beta, chemokine (C-C motif) ligand 5, and chemokine (C-X-C motif) ligand 10. These molecules activate both CD8⁺ T cells as well as natural killer cells and attract them to the tumor. It has been shown that in cancer cell lines, UV-inactivated SeV triggers the production of an intercellular adhesion molecule -1 (ICAM-1, CD54), which is a glycoprotein that serves as a ligand for macrophage-1 antigen (Mac-1) and lymphocyte function-associated antigen 1 (LFA-1 (integrin)). Mac-1 and LFA-1 are receptors found on leukocytes. This induced production happens through the activation of nuclear factor-κB downstream of the mitochondrial antiviral signaling pathway and the retinoic acid-inducible gene I. The increased concentration of ICAM-1 on the surface of cancer cells, which is triggered by SeV, increases the vulnerability of these cells to natural killer cells.{{cite journal |vauthors=Li S, Nishikawa T, Kaneda Y |title=Inactivated Sendai virus particle upregulates cancer cell expression of intercellular adhesion molecule-1 and enhances natural killer cell sensitivity on cancer cells |journal=Cancer Science |volume=108 |issue=12 |pages=2333–2341 |date=December 2017 |pmid=28945328 |pmc=5715349 |doi=10.1111/cas.13408 }}

Increased sialylation levels on the cell membrane have been linked to a heightened potential for invasion and metastasis in cancer cells. This correlation has been observed across various models, including murine,{{cite journal |vauthors=Yogeeswaran G, Salk PL |date=June 1981 |title=Metastatic potential is positively correlated with cell surface sialylation of cultured murine tumor cell lines |journal=Science |volume=212 |issue=4502 |pages=1514–6 |bibcode=1981Sci...212.1514Y |doi=10.1126/science.7233237 |pmid=7233237}}{{cite journal |vauthors=Passaniti A, Hart GW |date=June 1988 |title=Cell surface sialylation and tumor metastasis. Metastatic potential of B16 melanoma variants correlates with their relative numbers of specific penultimate oligosaccharide structures |journal=The Journal of Biological Chemistry |volume=263 |issue=16 |pages=7591–603 |doi=10.1016/S0021-9258(18)68540-0 |pmid=3372501 |doi-access=free}}{{cite journal |vauthors=Bresalier RS, Rockwell RW, Dahiya R, Duh QY, Kim YS |date=February 1990 |title=Cell surface sialoprotein alterations in metastatic murine colon cancer cell lines selected in an animal model for colon cancer metastasis |journal=Cancer Research |volume=50 |issue=4 |pages=1299–307 |pmid=2297775}} rat,{{cite journal |vauthors=Pearlstein E, Salk PL, Yogeeswaran G, Karpatkin S |date=July 1980 |title=Correlation between spontaneous metastatic potential, platelet-aggregating activity of cell surface extracts, and cell surface sialylation in 10 metastatic-variant derivatives of a rat renal sarcoma cell line |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=77 |issue=7 |pages=4336–9 |bibcode=1980PNAS...77.4336P |doi=10.1073/pnas.77.7.4336 |pmc=349829 |pmid=6933486 |doi-access=free}} and human,{{cite journal |vauthors=Benedetto A, Elia G, Sala A, Belardelli F |date=January 1989 |title=Hyposialylation of high-molecular-weight membrane glycoproteins parallels the loss of metastatic potential in wheat-germ agglutinin-resistant Friend leukemia cells |journal=International Journal of Cancer |volume=43 |issue=1 |pages=126–33 |doi=10.1002/ijc.2910430124 |pmid=2910824 |s2cid=24704777}} and is associated with the progression of malignancy. Some sialylation inhibitors can make cancer cells less malignant.{{cite journal |vauthors=Hsu CC, Lin TW, Chang WW, Wu CY, Lo WH, Wang PH, Tsai YC |title=Soyasaponin-I-modified invasive behavior of cancer by changing cell surface sialic acids |journal=Gynecologic Oncology |volume=96 |issue=2 |pages=415–22 |date=February 2005 |pmid=15661230 |doi=10.1016/j.ygyno.2004.10.010}}{{cite journal |vauthors=Chang WW, Yu CY, Lin TW, Wang PH, Tsai YC |title=Soyasaponin I decreases the expression of alpha2,3-linked sialic acid on the cell surface and suppresses the metastatic potential of B16F10 melanoma cells |journal=Biochemical and Biophysical Research Communications |volume=341 |issue=2 |pages=614–9 |date=March 2006 |pmid=16427612 |doi=10.1016/j.bbrc.2005.12.216}}{{cite journal |vauthors=Chiang CH, Wang CH, Chang HC, More SV, Li WS, Hung WC |title=A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin-mediated signaling |journal=Journal of Cellular Physiology |volume=223 |issue=2 |pages=492–9 |date=May 2010 |pmid=20112294 |doi=10.1002/jcp.22068 |s2cid=24218458}}

One possible explanation for the relationship between increased sialylation and a malignant phenotype is that sialylation results in a thick layer of coating on the cell membrane that masks cancer antigens and protects malignant cells from immune surveillance. The activity and cytotoxicity of NK cells is inhibited by the expression of sialic acids on the tumor cell surface.{{cite journal |vauthors=Cohen M, Elkabets M, Perlmutter M, Porgador A, Voronov E, Apte RN, Lichtenstein RG |title=Sialylation of 3-methylcholanthrene-induced fibrosarcoma determines antitumor immune responses during immunoediting |journal=Journal of Immunology |volume=185 |issue=10 |pages=5869–78 |date=November 2010 |pmid=20956342 |doi=10.4049/jimmunol.1001635 |s2cid=45698975 | doi-access = free}} Removal of sialic acid residues from the surface of tumor cells makes them available to NK cells and cytotoxic T lymphocytes and, therefore, reduces their growth potential. Moreover, treating tumor cells with sialidase improves activation of NK cell secretion of IFN-γ.

Some paramyxoviruses, including SeV encode and synthesize neuraminidase (sialidase), which can remove sialic acid residues from the surface of malignant cells. Hemagglutinin-neuraminidase (HN) is a single protein that induces hemagglutination and possesses neuraminidase (sialidase) activity. Neuraminidase (NA), a subunit of the HN protein, binds to and cleaves sialic acid from the cell surface.{{cite book |vauthors=Bossart KN, Fusco DL, Broder CC |chapter=Paramyxovirus Entry |title=Viral Entry into Host Cells |series=Advances in Experimental Medicine and Biology |volume=790 |pages=95–127 |date=2013 |location=New York, NY | publisher = Springer |pmid=23884588 |doi=10.1007/978-1-4614-7651-1_6 |pmc=8782154 |isbn=978-1-4614-7650-4}} NA also promotes cell fusion, which helps the nascent virions to avoid contact with host antibodies and thus enables the virus to spread within tissues.

Sialidase treatment of cells causes loss of sialic acid residues. This loss significantly increases the ability of malignant cells to activate cytotoxic T lymphocytes.{{cite journal |vauthors=Powell LD, Whiteheart SW, Hart GW |title=Cell surface sialic acid influences tumor cell recognition in the mixed lymphocyte reaction |journal=Journal of Immunology |volume=139 |issue=1 |pages=262–70 |date=July 1987 |doi=10.4049/jimmunol.139.1.262 |pmid=2953814|s2cid=25762755 |doi-access=free }} Variable sialidases can cause this effect, including NA from Newcastle disease virus that have been shown to cleave 2,3-, 2,6-,{{cite journal |vauthors=Tyagarajan K, Forte JG, Townsend RR |title=Exoglycosidase purity and linkage specificity: assessment using oligosaccharide substrates and high-pH anion-exchange chromatography with pulsed amperometric detection |journal=Glycobiology |volume=6 |issue=1 |pages=83–93 |date=January 1996 |pmid=8991514 |doi=10.1093/glycob/6.1.83 | doi-access = free}} and 2,8-linkages between sialic acid residues.{{cite journal |vauthors=Drzeniek R, Gauhe A |title=Differences in substrate specificity of myxovirus neuraminidases |journal=Biochemical and Biophysical Research Communications |volume=38 |issue=4 |pages=651–6 |date=February 1970 |pmid=5443707 |doi=10.1016/0006-291x(70)90630-3}} In vitro, there was no significant difference between NAs from Newcastle disease virus, SeV and mumps virus{{cite journal |vauthors=Brostrom MA, Bruening G, Bankowski RA |title=Comparison of neuraminidases of paramyxoviruses with immunologically dissimilar hemagglutinins |journal=Virology |volume=46 |issue=3 |pages=856–65 |date=December 1971 |pmid=4332979 |doi=10.1016/0042-6822(71)90086-9}} with respect to substrate specificity. These results suggest that treating a tumor with the virus results in desialylation of malignant cells, which contributes to increased anti-tumor immune surveillance. Therefore, the ability of SeV sialidase (NA) to remove sialic acid from the surface of malignant cells most likely helps to ensure the availability of tumor antigens for recognition by cytotoxic T lymphocytes.

Experiments with UV-inactivated SeV showed that NK cells are important in virus-mediated inhibition of tumor growth. This was shown in a mouse model of renal cancer, in which the anti-tumor effect of SeV was suppressed by reducing the number of NK cells by co-injection of specific antibodies.{{cite journal |vauthors=Fujihara A, Kurooka M, Miki T, Kaneda Y |title=Intratumoral injection of inactivated Sendai virus particles elicits strong antitumor activity by enhancing local CXCL10 expression and systemic NK cell activation |journal=Cancer Immunology, Immunotherapy |volume=57 |issue=1 |pages=73–84 |date=January 2008 |pmid=17602226 |doi=10.1007/s00262-007-0351-y |s2cid=8779015 |pmc=11030187 }}

The activation of NK requires several receptors, among which are natural killer proteins 46 (NKp46) and 44 (NKp44). Studies have shown that the only paramyxovirus protein that activates NK is HN.{{cite journal |vauthors=Jarahian M, Watzl C, Fournier P, Arnold A, Djandji D, Zahedi S, Cerwenka A, Paschen A, Schirrmacher V, Momburg F |title=Activation of natural killer cells by newcastle disease virus hemagglutinin-neuraminidase |journal=Journal of Virology |volume=83 |issue=16 |pages=8108–21 |date=August 2009 |pmid=19515783 |pmc=2715740 |doi=10.1128/JVI.00211-09}} HN protein binding to NKp46 and/or NKp44 results in the lysis of cells whose surfaces display the HN protein or its fragments.{{cite journal |vauthors=Arnon TI, Lev M, Katz G, Chernobrov Y, Porgador A, Mandelboim O |title=Recognition of viral hemagglutinins by NKp44 but not by NKp30 |journal=European Journal of Immunology |volume=31 |issue=9 |pages=2680–9 |date=September 2001 |pmid=11536166 |doi=10.1002/1521-4141(200109)31:9<2680::AID-IMMU2680>3.0.CO;2-A|s2cid=22437769 |doi-access=free }}{{cite journal |vauthors=Schirrmacher V, Haas C, Bonifer R, Ertel C |title=Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection |journal=Clinical Cancer Research |volume=3 |issue=7 |pages=1135–48 |date=July 1997 |pmid=9815793}} It can be assumed that NK activation and tumor suppression by UV-treated SeV are caused by interaction between HN belonging to SeV, and NKp46 and/or NKp44 receptors belonging to NK cells.

SeV even after UV inactivation, being injected intratumorally, can cause tumor infiltration by dendritic cells (DCs) and CD4+ and CD8+ T, and it also can cause enhancing of anti-tumor activity of these cells. Most likely, viral hemagglutinin-neuraminidase protein, highly contributes to the effect (see "Neuraminidase (NA) removal of sialic acid from the surface of malignant cells stimulates natural killers cells and cytotoxic T lymphocytes" section above).This hypothesis is based on two observations. First, the functional hemagglutinin-neuraminidase protein of the oncolytic Newcastle disease virus (NDV), which is a relative of SeV, has been shown to enhance the tumor-specific cytotoxic response of CD8+ T-cells and to increase the activity of CD4+ T-helper cells. Second, UV-inactivated NDV, which is can not replicate, promotes anti-tumor CTL response as well as does intact NDV, which can replicate. Since the hemagglutinin-neuraminidase proteins of the SeV and NDV viruses are highly homologous and function similarly, it is likely that the HN protein of the SeV virus can activate both CTL and natural killers cell responses. Most likely neuraminidase removal of sialic acid from the surface of malignant cells contributes to this effects.

UV-inactivated SeV can cause dendritic cells (DCs) to maturate and to infiltrate a tumor. Ex vivo infection of DCs with recombinant non-transmissible SeV induces maturation and activation of DCs{{cite book | vauthors = Ueda Y, Hasegawa M, Yonemitsu Y | chapter = Sendai Virus for Cancer Immunotherapy | title = Viral Applications of Green Fluorescent Protein | series = Methods in Molecular Biology | volume = 515 | pages = 299–308 | date = 2009 | publisher = Humana Press | location = Totowa, NJ | pmid = 19378123 | doi = 10.1007/978-1-59745-559-6_21 | isbn = 978-1-934115-87-9 }} within 60 minutes.{{cite journal | vauthors = Harada Y, Yonemitsu Y | title = Dramatic improvement of DC-based immunotherapy against various malignancies | journal = Frontiers in Bioscience | volume = 16 | issue = 6 | pages = 2233–2242 | date = June 2011 | pmid = 21622173 | doi = 10.2741/3850 | s2cid = 30195748 | doi-access = free }} When activated DCs that carry non-transmissible variants of SeV are administered, survival of animals injected with malignant melanoma,{{cite journal | vauthors = Shibata S, Okano S, Yonemitsu Y, Onimaru M, Sata S, Nagata-Takeshita H, Inoue M, Zhu T, Hasegawa M, Moroi Y, Furue M, Sueishi K | title = Induction of efficient antitumor immunity using dendritic cells activated by recombinant Sendai virus and its modulation by exogenous IFN-beta gene | journal = Journal of Immunology | volume = 177 | issue = 6 | pages = 3564–3576 | date = September 2006 | pmid = 16951315 | doi = 10.4049/jimmunol.177.6.3564 | s2cid = 20134438 | doi-access = free }}{{cite journal | vauthors = Okano S, Yonemitsu Y, Shirabe K, Kakeji Y, Maehara Y, Harada M, Yoshikai Y, Inoue M, Hasegawa M, Sueishi K | title = Provision of continuous maturation signaling to dendritic cells by RIG-I-stimulating cytosolic RNA synthesis of Sendai virus | journal = Journal of Immunology | volume = 186 | issue = 3 | pages = 1828–1839 | date = February 2011 | pmid = 21187441 | doi = 10.4049/jimmunol.0901641 | s2cid = 36653582 | doi-access = free }} colorectal cancer, squamous cell carcinoma,{{cite journal | vauthors = Yoneyama Y, Ueda Y, Akutsu Y, Matsunaga A, Shimada H, Kato T, Kubota-Akizawa M, Okano S, Shibata S, Sueishi K, Hasegawa M, Ochiai T, Yonemitsu Y | title = Development of immunostimulatory virotherapy using non-transmissible Sendai virus-activated dendritic cells | journal = Biochemical and Biophysical Research Communications | volume = 355 | issue = 1 | pages = 129–135 | date = March 2007 | pmid = 17292867 | doi = 10.1016/j.bbrc.2007.01.132 }} hepatic cancer, neuroblastoma, and prostate cancer is significantly improved. It has been shown that the administration of such DCs prior to tumor cell injection prevents metastasis of neuroblastoma and prostate adenocarcinoma to the lungs.{{cite journal | vauthors = Komaru A, Ueda Y, Furuya A, Tanaka S, Yoshida K, Kato T, Kinoh H, Harada Y, Suzuki H, Inoue M, Hasegawa M, Ichikawa T, Yonemitsu Y | title = Sustained and NK/CD4+ T cell-dependent efficient prevention of lung metastasis induced by dendritic cells harboring recombinant Sendai virus | journal = Journal of Immunology | volume = 183 | issue = 7 | pages = 4211–4219 | date = October 2009 | pmid = 19734206 | doi = 10.4049/jimmunol.0803845 | s2cid = 39194525 | doi-access = free }}{{cite journal | vauthors = Kato T, Ueda Y, Kinoh H, Yoneyama Y, Matsunaga A, Komaru A, Harada Y, Suzuki H, Komiya A, Shibata S, Hasegawa M, Hayashi H, Ichikawa T, Yonemitsu Y | title = RIG-I helicase-independent pathway in sendai virus-activated dendritic cells is critical for preventing lung metastasis of AT6.3 prostate cancer | journal = Neoplasia | volume = 12 | issue = 11 | pages = 906–914 | date = November 2010 | pmid = 21076616 | pmc = 2978913 | doi = 10.1593/neo.10732 }}

The enzymatic removal of sialic acids from the surface of dendritic cells by sialidase significantly promote the antigen-induced activation of naive T cells, while concurrently enhancing the resurgence of effector T cells. It is plausible that sialidase from Sendai virus (SeV) could execute this function.{{cite journal | vauthors = Edgar LJ, Thompson AJ, Vartabedian VF, Kikuchi C, Woehl JL, Teijaro JR, Paulson JC | title = Sialic Acid Ligands of CD28 Suppress Costimulation of T Cells | journal = ACS Central Science | volume = 7 | issue = 9 | pages = 1508–1515 | date = September 2021 | pmid = 34584952 | doi = 10.1021/acscentsci.1c00525 | pmc = 8461770 }} The removal not only improves antigen cross-presentation but boosts anti-tumor immune responses as well.{{Cite journal |last1=Silva |first1=Mariana |last2=Silva |first2=Zélia |last3=Marques |first3=Graça |last4=Ferro |first4=Tiago |last5=Gonçalves |first5=Márcia |last6=Monteiro |first6=Mauro |last7=van Vliet |first7=Sandra J. |last8=Mohr |first8=Elodie |last9=Lino |first9=Andreia C. |last10=Fernandes |first10=Alexandra R. |last11=Lima |first11=Flávia A. |last12=van Kooyk |first12=Yvette |last13=Matos |first13=Teresa |last14=Tadokoro |first14=Carlos E. |last15=Videira |first15=Paula A. |date=July 2016 |title=Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses |journal=Oncotarget |language=en |volume=7 |issue=27 |pages=41053–41066 |doi=10.18632/oncotarget.9419 |issn=1949-2553 |pmc=5173042 |pmid=27203391}} Dendritic cells with reduced sialylation form higher avidity interactions with CD8+ T cells.{{Cite journal |last1=Balneger |first1=N. |last2=Cornelissen |first2=L. A. M. |last3=Wassink |first3=M. |last4=Moons |first4=S. J. |last5=Boltje |first5=T. J. |last6=Bar-Ephraim |first6=Y. E. |last7=Das |first7=K. K. |last8=Søndergaard |first8=J. N. |last9=Büll |first9=C. |last10=Adema |first10=G. J. |date=February 2022 |title=Sialic acid blockade in dendritic cells enhances CD8+ T cell responses by facilitating high-avidity interactions |journal=Cellular and Molecular Life Sciences |language=en |volume=79 |issue=2 |page=98 |doi=10.1007/s00018-021-04027-x |issn=1420-682X |pmc=8799591 |pmid=35089436}}

SeV can replicate to high titers in human monocyte-derived DCs.{{cite journal |vauthors=Kiener R, Fleischmann M, Wiegand MA, Lemmermann NA, Schwegler C, Kaufmann C, Renzaho A, Thomas S, Felder E, Niller HH, Asbach B, Wagner R |title=Efficient Delivery of Human Cytomegalovirus T Cell Antigens by Attenuated Sendai Virus Vectors |journal=Journal of Virology |volume=92 |issue=15 |date=August 2018 |pmid=29769344 |pmc=6052310 |doi=10.1128/JVI.00569-18}} With the multiplicity of infection of 2, approximately 1/3 of the DCs begin to express encoded SeV proteins 8 hours after infection. This proportion increases to 2/3, 24 hours and decreases to 1/3, 48 hours after infection. SeV demonstrates high cytopathic effect on DCs; the virus can kill a third of DC even with a very low multiplicity of infection such as 0.5. Most important observation is that SeV infection triggers DC maturation, which is manifested in DC cell surface markers composition. The virus increases the expression of class I and class II molecules of the major histocompatibility complex (MHC) (HLA-A, HLA-B, HLA-C and HLADR), CD83, as well as costimulatory molecules CD40 and CD86.{{cite journal |vauthors=Hosoya N, Miura T, Kawana-Tachikawa A, Koibuchi T, Shioda T, Odawara T, Nakamura T, Kitamura Y, Kano M, Kato A, Hasegawa M, Nagai Y, Iwamoto A |title=Comparison between Sendai virus and adenovirus vectors to transduce HIV-1 genes into human dendritic cells |journal=Journal of Medical Virology |volume=80 |issue=3 |pages=373–82 |date=March 2008 |pmid=18205221 |doi=10.1002/jmv.21052 |s2cid=31337462}}File:GFPconstructs.jpg

Experiments with animal models have shown that, even after UV inactivation, SeV can block T-cell-mediated regulatory immunosuppression in tumors. The blocking mechanism is associated with the stimulation of SeV inactivated virions of interleukin 6 (IL-6) secretion by mature DCs. These effects lead to the eradication of most model tumors and inhibit the growth of the rest. It has been shown that F protein alone can trigger IL-6 production in DC in a fusion-independent manner.

File:Sendai Virus organ infection specificity.pngs in vivo in a murine model of hepatoma which has been xenografted. ]]

File:ConstructsofCharlesRussellab.jpg

File:Non invasive SeV imaging variable constructs.png of Sendai virus infection in the respiratory tracts of living mice]]

SeV has been known to the research community since the late 1950s and has been widely used to create numerous variants of genetically engineered constructs, including vectors for transgene delivery.{{Cite book | veditors = Nagai Y |title=Sendai virus vector: advantages and applications |date=2014-01-31 |isbn=978-4-431-54556-9 |location=Tokyo | publisher = Springer |oclc=870271420 }}{{cite book | vauthors = Parks CL | chapter = Replication-Competent Viral Vectors for Vaccine Delivery |date=2017 | title = Human Vaccines |pages=25–63 |publisher=Elsevier |language=en |doi=10.1016/b978-0-12-802302-0.00001-7 |isbn=978-0-12-802302-0 }} Creation of SeV genetic constructs is easier compared to other viruses, many SeV genes have a transcriptional initiation and termination signals. Therefore, constructing a recombinant virus is straightforward; the foreign gene can be introduced into the viral genome by replacing or adding viral protein expressing gene(s). SeV can include a foreign gene or even multiple genes of large size. It has been demonstrated that a gene of more than 3 kb can be inserted and expressed in SeV. Due to exclusively cytoplasmic replication, the virus does not carry the risk of genetic integration into the host genomes, which is a problem for many other viral vectors. The genome of SeV as genomes of other non segmented negative-stranded RNA viruses has a low rate of homologous recombination and evolves comparatively slowly. Multiple reasons for this genomic stability exist: (1) the genome is nonsegmented, therefore cannot undergo genetic reassortment, (2) each protein and each amino acid has an important function. Therefore, any new genetic insertion, substitution or deletion would lead to a decrease or total loss of function that would in turn cause the new virus variant to be less viable. (3) Sendai virus belongs to a category of viruses that are governed by the “rule of six”. SeV genome as genomes of other paramyxoviruses mainly include six genes, which encode for six major proteins. Low rate of homologous RNA recombination in paramyxoviruses probably results from this unusual genomic requirement for polyhexameric length (6n+0). Natural high genomic stability of SeV is a positive feature for it potential use as a vaccine vector or as an oncolytic agent. For any clinical or industrial applications, it is important that SeV genomic and inserted foreign genes would be expressed in a stable way. Due to SeV genetic stability, multiple serial passages of the virus construct in cell cultures or embryonated chicken eggs without drastic genomic changes are possible. SeV constructs are known to stably express a wide variety of heterologous antigens.

The reverse genetics system to rescue Sendai virus was created and published in 1995.{{cite journal |vauthors=Garcin D, Pelet T, Calain P, Roux L, Curran J, Kolakofsky D |title=A highly recombinogenic system for the recovery of infectious Sendai paramyxovirus from cDNA: generation of a novel copy-back nondefective interfering virus |journal=The EMBO Journal |volume=14 |issue=24 |pages=6087–94 |date=December 1995 |pmid=8557028 |pmc=394733 |doi=10.1002/j.1460-2075.1995.tb00299.x}} Since then a number of modifications and improvements were described for representatives of Mononegavirales,{{cite journal |vauthors=Pfaller CK, Cattaneo R, Schnell MJ |title=Reverse genetics of Mononegavirales: How they work, new vaccines, and new cancer therapeutics |journal=Virology |volume=479 |pages=331–344 |date=May 2015 |pmid=25702088 |pmc=4557643 |doi=10.1016/j.virol.2015.01.029 |series=60th Anniversary Issue}} Paramyxoviridae in general,{{cite journal |vauthors=Beaty SM, Park A, Won ST, Hong P, Lyons M, Vigant F, Freiberg AN, tenOever BR, Duprex WP, Lee B |title=Paramyxoviridae Reverse Genetics Systems |journal=mSphere |volume=2 |issue=2 |date=March 2017 |pmid=28405630 |pmc=5371697 |doi=10.1128/mSphere.00376-16}}{{cite journal |vauthors=Liu H, Albina E, Gil P, Minet C, de Almeida RS |title=Two-plasmid system to increase the rescue efficiency of paramyxoviruses by reverse genetics: The example of rescuing Newcastle Disease Virus |journal=Virology |volume=509 |pages=42–51 |date=September 2017 |pmid=28595094 |doi=10.1016/j.virol.2017.06.003 | doi-access = free}}{{cite journal |vauthors=Liu H, de Almeida RS, Gil P, Albina E |title=Comparison of the efficiency of different newcastle disease virus reverse genetics systems |journal=Journal of Virological Methods |volume=249 |pages=111–116 |date=November 2017 |pmid=28867302 |doi=10.1016/j.jviromet.2017.08.024}} and for Sendai virus in particular.{{cite book |vauthors=Bajimaya S, Hayashi T, Takimoto T |title=Reverse Genetics of RNA Viruses |chapter=Rescue of Sendai Virus from Cloned cDNA |series=Methods in Molecular Biology |volume=1602 |pages=103–110 |date=2017 |publisher=Springer |location=New York, NY |pmid=28508216 |doi=10.1007/978-1-4939-6964-7_7 |isbn=978-1-4939-6962-3}} The entire length of the vector SeV genome, including transgenes, has to be arranged in multiples of six nucleotides (the so-called "rule of six").File:Trafficking-of-Sendai-Virus-Nucleocapsids-Is-Mediated-by-Intracellular-Vesicles-pone.0010994.s005.ogvs is mediated by intracellular vesicles|left]]

Recombinant SeV variants has been constructed by introducing new genes and/or by deleting some viral genes such as F, M, and HN from the SeV genome.{{cite journal | vauthors = Sugiyama M, Kakeji Y, Tsujitani S, Harada Y, Onimaru M, Yoshida K, Tanaka S, Emi Y, Morita M, Morodomi Y, Hasegawa M, Maehara Y, Yonemitsu Y | title = Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites | journal = Molecular Cancer Therapeutics | volume = 10 | issue = 3 | pages = 540–549 | date = March 2011 | pmid = 21209070 | doi = 10.1158/1535-7163.MCT-10-0479 | s2cid = 37616710 | doi-access = free | hdl = 2324/25486 | hdl-access = free }}{{cite journal | vauthors = Yoshizaki M, Hironaka T, Iwasaki H, Ban H, Tokusumi Y, Iida A, Nagai Y, Hasegawa M, Inoue M | title = Naked Sendai virus vector lacking all of the envelope-related genes: reduced cytopathogenicity and immunogenicity | journal = The Journal of Gene Medicine | volume = 8 | issue = 9 | pages = 1151–1159 | date = September 2006 | pmid = 16841365 | doi = 10.1002/jgm.938 | s2cid = 39942120 }}{{cite journal | vauthors = Inoue M, Tokusumi Y, Ban H, Kanaya T, Shirakura M, Tokusumi T, Hirata T, Nagai Y, Iida A, Hasegawa M | title = A new Sendai virus vector deficient in the matrix gene does not form virus particles and shows extensive cell-to-cell spreading | journal = Journal of Virology | volume = 77 | issue = 11 | pages = 6419–6429 | date = June 2003 | pmid = 12743299 | pmc = 155001 | doi = 10.1128/JVI.77.11.6419-6429.2003 }} Reporter genes, such as those that are coding luciferase,{{cite journal |vauthors=Mostafa HH, Vogel P, Srinivasan A, Russell CJ |date=September 2016 |title=Non-invasive Imaging of Sendai Virus Infection in Pharmacologically Immunocompromised Mice: NK and T Cells, but not Neutrophils, Promote Viral Clearance after Therapy with Cyclophosphamide and Dexamethasone |journal=PLOS Pathogens |volume=12 |issue=9 |pages=e1005875 |doi=10.1371/journal.ppat.1005875 |pmc=5010285 |pmid=27589232 |doi-access=free}}{{cite journal |vauthors=Hasan MK, Kato A, Shioda T, Sakai Y, Yu D, Nagai Y |date=November 1997 |title=Creation of an infectious recombinant Sendai virus expressing the firefly luciferase gene from the 3' proximal first locus |journal=The Journal of General Virology |volume=78 |issue=11 |pages=2813–20 |doi=10.1099/0022-1317-78-11-2813 |pmid=9367367 |doi-access=free}} green{{cite journal |vauthors=Agungpriyono DR, Yamaguchi R, Uchida K, Tohya Y, Kato A, Nagai Y, Asakawa M, Tateyama S |date=February 2000 |title=Green fluorescent protein gene insertion of Sendai Virus infection in nude mice: possibility as an infection tracer |journal=The Journal of Veterinary Medical Science |volume=62 |issue=2 |pages=223–8 |doi=10.1292/jvms.62.223 |pmid=10720198 |doi-access=free}}{{cite journal |vauthors=Miyazaki M, Segawa H, Yamashita T, Zhu Y, Takizawa K, Hasegawa M, Taira H |date=2010-11-23 |title=Construction and characterization of a fluorescent sendai virus carrying the gene for envelope fusion protein fused with enhanced green fluorescent protein |journal=Bioscience, Biotechnology, and Biochemistry |volume=74 |issue=11 |pages=2293–8 |doi=10.1271/bbb.100511 |pmid=21071846 |s2cid=43669142 |doi-access=free}} or red fluorescent proteins can be inserted in different locations in the viral genome. These locations include positions upstream of the N gene, between the N and P genes,{{cite journal | vauthors = Touzelet O, Loukili N, Pelet T, Fairley D, Curran J, Power UF | title = De novo generation of a non-segmented negative strand RNA virus with a bicistronic gene | journal = Virus Research | volume = 140 | issue = 1–2 | pages = 40–48 | date = March 2009 | pmid = 19084562 | doi = 10.1016/j.virusres.2008.10.019 }} between P and M, M and F,{{cite journal |vauthors=Strähle L, Marq JB, Brini A, Hausmann S, Kolakofsky D, Garcin D |date=November 2007 |title=Activation of the beta interferon promoter by unnatural Sendai virus infection requires RIG-I and is inhibited by viral C proteins |journal=Journal of Virology |volume=81 |issue=22 |pages=12227–37 |doi=10.1128/JVI.01300-07 |pmc=2169027 |pmid=17804509}}{{cite journal |vauthors=Gosselin-Grenet AS, Mottet-Osman G, Roux L |date=September 2010 |title=Sendai virus particle production: basic requirements and role of the SYWST motif present in HN cytoplasmic tail |journal=Virology |volume=405 |issue=2 |pages=439–447 |doi=10.1016/j.virol.2010.06.030 |pmid=20633915 |doi-access=free}} F and HN, HN and L, and after the L gene.

SeV constructs have also been created with a modified protease cleavage site in fusion protein (F). The SeV F protein is a type I membrane glycoprotein that is synthesized as an inactive precursor (F₀) that must be activated by proteolytic cleavage at residue arginine-116. After the cleavage F₀ precursor yields two disulfide-linked subunits F₁ and F₂. The proteolytic cleavage site can be changed, so other host proteases would be capable to process F₀.{{cite journal |vauthors=Rawling J, Cano O, Garcin D, Kolakofsky D, Melero JA |title=Recombinant Sendai viruses expressing fusion proteins with two furin cleavage sites mimic the syncytial and receptor-independent infection properties of respiratory syncytial virus |journal=Journal of Virology |volume=85 |issue=6 |pages=2771–80 |date=March 2011 |pmid=21228237 |pmc=3067931 |doi=10.1128/jvi.02065-10}}{{cite journal |vauthors=Rawling J, García-Barreno B, Melero JA |title=Insertion of the two cleavage sites of the respiratory syncytial virus fusion protein in Sendai virus fusion protein leads to enhanced cell-cell fusion and a decreased dependency on the HN attachment protein for activity |journal=Journal of Virology |volume=82 |issue=12 |pages=5986–98 |date=June 2008 |pmid=18385247 |pmc=2395136 |doi=10.1128/jvi.00078-08}}

Sendai virus based vector system that can deliver CRISPR/Cas9 for efficient gene editing was created.{{cite journal |vauthors=Park A, Hong P, Won ST, Thibault PA, Vigant F, Oguntuyo KY, Taft JD, Lee B |title=Sendai virus, an RNA virus with no risk of genomic integration, delivers CRISPR/Cas9 for efficient gene editing |journal=Molecular Therapy: Methods & Clinical Development |volume=3 |pages=16057 |date=2016-08-24 |pmid=27606350 |pmc=4996130 |doi=10.1038/mtm.2016.57}}

A variety of Sendai virus constructs carrying reporter genes were developed for non-invasive imaging of the virus infection in animals. They allow to study dynamics of SeV spread and clearance. Some of these constructs were designed to deliver luciferase genes, some to deliver green fluorescent protein (GFP), others to deliver red fluorescent protein (RFP).

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File:Sendai virus minigenome.jpgThe Sendai virus minigenome is a shortened version of its viral genome, in which some portions of the coding sequences of the virus have been removed. The removed genes can be replaced with a foreign trans-gene of interest.{{cite journal | vauthors = Corral T, Ver LS, Mottet G, Cano O, García-Barreno B, Calder LJ, Skehel JJ, Roux L, Melero JA | title = High level expression of soluble glycoproteins in the allantoic fluid of embryonated chicken eggs using a Sendai virus minigenome system | journal = BMC Biotechnology | volume = 7 | issue = 1 | pages = 17 | date = April 2007 | pmid = 17411439 | pmc = 1852797 | doi = 10.1186/1472-6750-7-17 | doi-access = free }} The minigenome can be multiplied in cells expressing a minimal set of complementary viral proteins or infected with a homologous wild-type helper virus. Sendai virus minigenomes are used to produce recombinant proteins of interest, and in a vector system to reprogram cells into pluripotent stem cells (iPSCs). A Sendai virus minigenome lacking Fusion protein, but expressing Emerald Green Fluorescent Protein (EmGFP) as a reporter was found to be an efficient gene delivery vector in several human pancreatic cancer cells.{{cite journal | vauthors = Grygoryev D, Ekstrom T, Manalo E, Link JM, Alshaikh A, Keith D, Allen-Petersen BL, Sheppard B, Morgan T, Soufi A, Sears RC, Kim J | title = Sendai virus is robust and consistent in delivering genes into human pancreatic cancer cells | journal = Heliyon | volume = 10 | issue = 5 | pages = e27221 | date = March 2024 | pmid = 38463758 | pmc = 10923719 | doi = 10.1016/j.heliyon.2024.e27221 | doi-access = free | bibcode = 2024Heliy..1027221G }}

To integrate a gene fragment of interest into the Sendai Virus genome, the following protocol might be used.

The amplified gene fragment is inserted into a Sendai Virus vector lacking the F protein (SeV/ΔF). The recovery and amplification of SeV/ΔF vectors proceed as follows:

• Transfection: 293T cells are transfected with the pSeV/ΔF template containing the transgene of interest, along with plasmids that encode the T7 RNA polymerase and the viral genes NP, P, F5R (a modified F protein), and L.
• Cultivation: Post-transfection, the cells are incubated and cultured for 1 to 3 days to produce the initial SeV/ΔF vector.
• Propagation: The vector is then propagated in LLC-MK2/F7/A cells, a specialized cell line of LLC-MK2 that expresses the Sendai virus F protein, in a medium that includes trypsin.
• Titer Quantification: The titers of the harvested SeV vector are determined by measuring the cell infectious units (CIU) per milliliter through immunostaining with anti-SeV rabbit polyclonal serum.

File:Soluble glycoprotein production system.jpg

Researchers have developed an innovative method to efficiently produce substantial quantities of heterologous viral glycoproteins within the allantoic cavity of embryonated chicken eggs. This technique utilizes a Sendai virus minigenome as a vector to express soluble variants of specific proteins, notably the human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV) fusion (F) proteins. These proteins are engineered without their transmembrane and cytoplasmic domains, facilitating their solubility.

Overview of the Methodology:

• Rescue of Sendai Virus Minigenomes: The process begins with the rescue of Sendai virus minigenomes that encode the target proteins. This step is conducted in cell cultures, assisted by the wild-type Sendai virus, which acts as a helper virus.

• Propagation in Embryonated Eggs: Subsequently, the engineered viruses are propagated within the allantoic cavity of chicken embryonated eggs. This environment is conducive to the viruses’ replication and protein production. To enhance yields, the process may undergo several iterations across different generations of eggs.
• Yield Enhancement: Comparative studies have demonstrated that this method yields protein quantities that are 5 to 10 times greater than those produced in cell culture supernatants infected with vaccinia virus recombinants.

File:Sendai virus for iPSCs.jpg

One of the latest applications of SeV-based vectors is the reprogramming of somatic cells into induced pluripotent stem cells.{{cite journal |vauthors=Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M |title=Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome |journal=Proceedings of the Japan Academy. Series B, Physical and Biological Sciences |volume=85 |issue=8 |pages=348–62 |date=2009 |pmid=19838014 |pmc=3621571 |doi=10.2183/pjab.85.348 |bibcode=2009PJAB...85..348F}}{{cite journal |vauthors=Ban H, Nishishita N, Fusaki N, Tabata T, Saeki K, Shikamura M, Takada N, Inoue M, Hasegawa M, Kawamata S, Nishikawa S |title=Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=108 |issue=34 |pages=14234–9 |date=August 2011 |pmid=21821793 |pmc=3161531 |doi=10.1073/pnas.1103509108 |bibcode=2011PNAS..10814234B| doi-access = free }} The SeV vector with a mutation that is responsible for temperature-sensitive phenotype was created to facilitate the erasure of the vector genome in a cell line. Temperature sensitive mutants of SeV encoding human OCT3/4, SOX2, KLF4 and c-MYC genes are used to infect human donor cells, but the resulting iPSCs became trans-gene free.{{cite journal |vauthors=Fujie Y, Fusaki N, Katayama T, Hamasaki M, Soejima Y, Soga M, Ban H, Hasegawa M, Yamashita S, Kimura S, Suzuki S, Matsuzawa T, Akari H, Era T |title=New type of Sendai virus vector provides transgene-free iPS cells derived from chimpanzee blood |journal=PLOS ONE |volume=9 |issue=12 |pages=e113052 |date=2014-12-05 |pmid=25479600 |pmc=4257541 |doi=10.1371/journal.pone.0113052 |bibcode=2014PLoSO...9k3052F| doi-access = free }} One possible source of donor cells are human cord blood-derived hematopoietic stem cells stimulated with cytokines. Among these cells SeV achieves high transgene expression in CD34+ cells subset.{{cite journal |vauthors=Jin CH, Kusuhara K, Yonemitsu Y, Nomura A, Okano S, Takeshita H, Hasegawa M, Sueishi K, Hara T |title=Recombinant Sendai virus provides a highly efficient gene transfer into human cord blood-derived hematopoietic stem cells |journal=Gene Therapy |volume=10 |issue=3 |pages=272–7 |date=February 2003 |pmid=12571635 |doi=10.1038/sj.gt.3301877 |s2cid=22415369 | doi-access = free}} Another source—human primary PBMC, according to [https://www.takarabio.com/learning-centers/stem-cell-research/technical-notes/pluripotent-stem-cells/reprogramming-pbmcs a technical note of TaKaRa] human primary PBMC from donors blood can be directly reprogrammed into iPSC during 21 days period. Patient and healthy donors peripheral blood also can be a source of CD34+ cells subset that can be reprogrammed into iPSC.{{cite journal | vauthors = Okumura T, Horie Y, Lai CY, Lin HT, Shoda H, Natsumoto B, Fujio K, Kumaki E, Okano T, Ono S, Tanita K, Morio T, Kanegane H, Hasegawa H, Mizoguchi F, Kawahata K, Kohsaka H, Moritake H, Nunoi H, Waki H, Tamaru SI, Sasako T, Yamauchi T, Kadowaki T, Tanaka H, Kitanaka S, Nishimura K, Ohtaka M, Nakanishi M, Otsu M | title = Robust and highly efficient hiPSC generation from patient non-mobilized peripheral blood-derived CD34⁺ cells using the auto-erasable Sendai virus vector | journal = Stem Cell Research & Therapy | volume = 10 | issue = 1 | pages = 185 | date = June 2019 | pmid = 31234949 | pmc = 6591940 | doi = 10.1186/s13287-019-1273-2 | doi-access = free }} PBMC derived T cells activated for 5 days with anti-CD3 antibody and IL-2 also can be used for the purpose.{{cite journal |vauthors=Seki T, Yuasa S, Fukuda K |title=Generation of induced pluripotent stem cells from a small amount of human peripheral blood using a combination of activated T cells and Sendai virus |journal=Nature Protocols |volume=7 |issue=4 |pages=718–28 |date=March 2012 |pmid=22422317 |doi=10.1038/nprot.2012.015 |s2cid=41397031}} In addition, human fibroblasts can be utilized for iPSC creation. The system for such reprogramming is commercially available from ThermoFisher Scientific as CTS™ CytoTune™-iPS 2.1 Sendai Reprogramming Kit, Catalog number: A34546.{{Cite web |url=https://www.thermofisher.com/order/catalog/product/A34546?SID=srch-srp-A34546 |title=CTS CytoTune-iPS 2.1 Sendai Reprogramming Kit - Thermo Fisher Scientific |website=www.thermofisher.com |access-date=2019-08-13}} The relevant video that explains the process of the vector creation entitled "[https://www.youtube.com/watch?time_continue=14&v=Br1AMR7ohwI&feature=emb_logo How Does Sendai Virus Reprogram Cells?] " is available online. Deriving naive human iPSCs using Sendai virus vectors presents challenges, but these are gradually being overcome.{{Cite journal |last1=Charlesworth |first1=Carsten T. |last2=Nakauchi |first2=Hiromitsu |date=November 2022 |title=An optimized Sendai viral vector platform for reprogramming to naive pluripotency |journal=Cell Reports Methods |language=en |volume=2 |issue=11 |pages=100349 |doi=10.1016/j.crmeth.2022.100349 |pmc=9701616 |pmid=36452874}}

SeV vector is one of the most efficient vectors for airway gene transfer. In its natural hosts, like mice, and non-natural hosts, like sheep, SeV-mediated foreign gene expression can be visualized in lungs. This expression is transient: intensive during a few days after the first SeV administration but is returning to baseline, zero values, by day 14. After the second administration, the expression of trans genes is getting reduced by 60% when compared with levels achieved after a first dose.

A replication-defective and persistent Sendai virus can be used as a platform for a durable expression of microRNAs, which were able to inhibit expression of targeted genes.

{{cite journal | vauthors = Sano M, Nakasu A, Ohtaka M, Nakanishi M | title = A Sendai Virus-Based Cytoplasmic RNA Vector as a Novel Platform for Long-Term Expression of MicroRNAs | language = English | journal = Molecular Therapy. Methods & Clinical Development | volume = 15 | pages = 371–382 | date = December 2019 | pmid = 31828179 | doi = 10.1016/j.omtm.2019.10.012 | pmc = 6889074 }}

SeV has several features that are important in a vector for a successful vaccine: the virus does not integrate into the host genome, it does not undergo genetic recombination, it replicates only in the cytoplasm without DNA intermediates or a nuclear phase. SeV, as all other representatives of family Paramyxoviridae, is genetically stable and evolves very slowly. SeV genome can accommodate foreign genes in multiple intergenic positions and the SeV genome is suitable for introducing genes encoding the envelope glycoproteins of pathogenic viruses. For vaccination purpose the virus-based constructs could be delivered in a form of nasal drops, which may be beneficial in inducing a mucosal immune response. This form of vaccination is more immunogenic than intramuscular considering pre-existing anti-SeV antibodies.{{cite journal | vauthors = Moriya C, Horiba S, Kurihara K, Kamada T, Takahara Y, Inoue M, Iida A, Hara H, Shu T, Hasegawa M, Matano T | title = Intranasal Sendai viral vector vaccination is more immunogenic than intramuscular under pre-existing anti-vector antibodies | journal = Vaccine | volume = 29 | issue = 47 | pages = 8557–8563 | date = November 2011 | pmid = 21939708 | doi = 10.1016/j.vaccine.2011.09.028 }} Sendai virus-based constructs can induce durable, mucosal, B-cell, and T-cell immune responses. The virus genome has high similarity with human parainfluenza virus 1 (HPIV-1) and the two viruses share common antigenic determinants. The study that was published in 2011 demonstrated that SeV neutralizing antibodies (which were formed due to human parainfluenza virus type 1 past infection) can be detected in 92.5% of human subjects worldwide with a median EC₅₀ titer of 60.6 and values ranging from 5.9–11,324. Low anti-SeV antibodies background does not block the ability of SeV-base vaccine to promote antigen-specific T cell immunity.

Wild type, attenuated SeV has been used in clinical trials involving both adults and children to immunize against HPIV-1.The virus administration in the form of nasal drops in doses ranging from 5 × 10⁵ 50% embryo infectious dose (EID50) to 5 × 10⁷ induced the production of neutralizing antibodies to the human virus without any measurable side effects. The results of these trials represent an evidence of safety for humans of replication competent Sendai virus administration. SeV antibodies that cross-reactive with HPIV-1 antibodies are present in most people, however, majority of people do not have high titer of these antibodies. The study that was published in 2011 demonstrated that SeV neutralizing antibodies (which were formed due to HPIV-1 past infection) can be detected in 92.5% subjects worldwide with a median EC₅₀ titer of 60.6 and values ranging from 5.9–11,324. Low anti-SeV antibodies background does not block the ability of SeV-base vaccine to promote antigen-specific T cell immunity.

The development of T cell-based AIDS vaccines using Sendai virus vectors is taking place reached phase II clinical trial. Evaluation of the safety and immunogenicity of an intranasally administered replication-competent Sendai Virus–vectored HIV Type 1 gag vaccine demonstrated: induction of potent T-Cell and antibody responses in prime-boost regimens.{{cite journal | vauthors = Nyombayire J, Anzala O, Gazzard B, Karita E, Bergin P, Hayes P, Kopycinski J, Omosa-Manyonyi G, Jackson A, Bizimana J, Farah B, Sayeed E, Parks CL, Inoue M, Hironaka T, Hara H, Shu T, Matano T, Dally L, Barin B, Park H, Gilmour J, Lombardo A, Excler JL, Fast P, Laufer DS, Cox JH | title = First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens | journal = The Journal of Infectious Diseases | volume = 215 | issue = 1 | pages = 95–104 | date = January 2017 | pmid = 28077588 | pmc = 5225252 | doi = 10.1093/infdis/jiw500 }}{{cite journal | vauthors = Seki S, Matano T | title = Development of a Sendai virus vector-based AIDS vaccine inducing T cell responses | journal = Expert Review of Vaccines | volume = 15 | issue = 1 | pages = 119–127 | date = 2016 | pmid = 26512881 | doi = 10.1586/14760584.2016.1105747 | s2cid = 27197590 }}

Sendai virus was also used as a backbone for vaccine against respiratory syncytial virus (HRSV).{{cite journal |vauthors=Russell CJ, Hurwitz JL |title=Sendai virus as a backbone for vaccines against RSV and other human paramyxoviruses |journal=Expert Review of Vaccines |volume=15 |issue=2 |pages=189–200 |date=2015-12-09 |pmid=26648515 |pmc=4957581 |doi=10.1586/14760584.2016.1114418}}{{cite journal |vauthors=Jones BG, Sealy RE, Rudraraju R, Traina-Dorge VL, Finneyfrock B, Cook A, Takimoto T, Portner A, Hurwitz JL |title=Sendai virus-based RSV vaccine protects African green monkeys from RSV infection |journal=Vaccine |volume=30 |issue=5 |pages=959–68 |date=January 2012 |pmid=22119594 |pmc=3256274 |doi=10.1016/j.vaccine.2011.11.046}} This virus (HRSV), is a major cause of lower respiratory tract infections and hospital visits during infancy and childhood. It was shown that administration of SeV-based RSV vaccine protects cotton rats{{cite journal |vauthors=Zhan X, Slobod KS, Jones BG, Sealy RE, Takimoto T, Boyd K, Surman S, Russell CJ, Portner A, Hurwitz JL |title=Sendai virus recombinant vaccine expressing a secreted, unconstrained respiratory syncytial virus fusion protein protects against RSV in cotton rats |journal=International Immunology |volume=27 |issue=5 |pages=229–36 |date=May 2015 |pmid=25477211 |pmc=4406265 |doi=10.1093/intimm/dxu107 |url=}} and African green monkeys from this viral infection. The [https://clinicaltrials.gov/ct2/show/study/NCT03473002 HRSV phase I clinical trial] was completed in adults. It demonstrated high safety of the SeV-based construct that expressed HRSV envelope F glycoprotein.

SeV is currently used in preclinical studies as a backbone vector for vaccine against tuberculosis. Mucosal vaccination with SeV construct generates memory CD8 T cell immunity and promotes protection against Mycobacterium tuberculosis in mice.{{cite journal |vauthors=Hu Z, Jiang W, Gu L, Qiao D, Shu T, Lowrie DB, Lu SH, Fan XY |title=Heterologous prime-boost vaccination against tuberculosis with recombinant Sendai virus and DNA vaccines |journal=Journal of Molecular Medicine |volume=97 |issue=12 |pages=1685–1694 |date=December 2019 |pmid=31786669 |doi=10.1007/s00109-019-01844-3 |s2cid=208359634 | doi-access = free}}{{cite journal |vauthors=Hu Z, Gu L, Li CL, Shu T, Lowrie DB, Fan XY |title=The Profile of T Cell Responses in Bacille Calmette-Guérin-Primed Mice Boosted by a Novel Sendai Virus Vectored Anti-Tuberculosis Vaccine |journal=Frontiers in Immunology |volume=9 |pages=1796 |date=2018 |pmid=30123219 |pmc=6085409 |doi=10.3389/fimmu.2018.01796 | doi-access = free}}{{Cite journal |last1=Hu |first1=Zhidong |last2=Xia |first2=Jingxian |last3=Wu |first3=Juan |last4=Zhao |first4=Huimin |last5=Ji |first5=Ping |last6=Gu |first6=Ling |last7=Gu |first7=Wenfei |last8=Chen |first8=Zhenyan |last9=Xu |first9=Jinchuan |last10=Huang |first10=Xuejiao |last11=Ma |first11=Jian |last12=Chen |first12=Anke |last13=Li |first13=Jixi |last14=Shu |first14=Tsugumine |last15=Fan |first15=Xiao-Yong |date=December 2024 |title=A multistage Sendai virus vaccine incorporating latency-associated antigens induces protection against acute and latent tuberculosis |journal=Emerging Microbes & Infections |volume=13 |issue=1 |pages=2300463 |doi=10.1080/22221751.2023.2300463 |issn=2222-1751 |pmid=38164736|pmc=10769537 }}

For effective prevention of infections caused by SARS-CoV-2, the ability of the vaccine to stimulate the mucosal immunity of the upper respiratory tract, including the nasal cavity, might be highly important. Such immunity is able to strengthen the antiviral barrier in the upper respiratory tract and provide reliable protection against COVID-19.{{cite journal | vauthors = Moreno-Fierros L, García-Silva I, Rosales-Mendoza S | title = Development of SARS-CoV-2 vaccines: should we focus on mucosal immunity? | journal = Expert Opinion on Biological Therapy | volume = 20 | issue = 8 | pages = 831–836 | date = August 2020 | pmid = 32380868 | doi = 10.1080/14712598.2020.1767062 | s2cid = 218556295 | doi-access = free }}{{cite journal | vauthors = Travis CR | title = As Plain as the Nose on Your Face: The Case for A Nasal (Mucosal) Route of Vaccine Administration for Covid-19 Disease Prevention | journal = Frontiers in Immunology | volume = 11 | pages = 591897 | date = 2020-09-30 | pmid = 33117404 | pmc = 7561361 | doi = 10.3389/fimmu.2020.591897 | doi-access = free }} It has been demonstrated that intranasally administered SeV can elicit strong mucosal immunity. Thus, mucosal vaccination with SeV generates robust IgA and IgG antibodies production by nasal-associated lymphoid tissue and by lungs of cotton rats. These antibodies facilitated rapid protection against human parainfluenza virus-type 1.{{cite journal | vauthors = Sealy R, Jones BG, Surman SL, Hurwitz JL | title = Robust IgA and IgG-producing antibody forming cells in the diffuse-NALT and lungs of Sendai virus-vaccinated cotton rats associate with rapid protection against human parainfluenza virus-type 1 | journal = Vaccine | volume = 28 | issue = 41 | pages = 6749–6756 | date = September 2010 | pmid = 20682364 | pmc = 2950074 | doi = 10.1016/j.vaccine.2010.07.068 }}

In China, Fudan University in collaboration with Pharma Co. Ltd. is engaged in development of the vaccine for COVID-19 prevention. SeV serves as a backbone vector in the project [https://www.bioworld.com/articles/433331-increasing-number-of-biopharma-drugs-target-covid-19-as-virus-spreads]. Researchers from the Fudan University have significant experience working with SeV vectors; they created SeV based vaccine for tuberculosis prevention, which is in pre-clinical testing.{{cite journal |vauthors=Hu Z, Wong KW, Zhao HM, Wen HL, Ji P, Ma H, Wu K, Lu SH, Li F, Li ZM, Shu T, Xu JQ, Lowrie DB, Fan XY |date=May 2017 |title=Sendai Virus Mucosal Vaccination Establishes Lung-Resident Memory CD8T Cell Immunity and Boosts BCG-Primed Protection against TB in Mice |journal=Molecular Therapy |volume=25 |issue=5 |pages=1222–1233 |doi=10.1016/j.ymthe.2017.02.018 |pmc=5417795 |pmid=28342639}} There are two Sendai virus strains in China that were described in scientific publications. One of them is BB1 strain, which derived from the [https://www.atcc.org/products/all/PTA-121432.aspx Moscow virus strain] and has less than 20 non-synomic substitutions compared to Moscow strain. The strain BB1 was given to the researchers of Institute of Viral Disease Control and Prevention, Beijing, China by researchers of Ivanovsky Institute of Virology, Moscow, Russia in the 1960s. Another strain is Tianjin strain, isolated in China in 2008. One of these strains was used for creation of replication deficient SeV85AB construct that is lacking fusion protein (F) but has inserted sequence encoding immunodominant antigen of Mycobacterium tuberculosis.{{cite journal | vauthors = Liang Y, Wu X, Zhang J, Xiao L, Yang Y, Bai X, Yu Q, Li Z, Bi L, Li N, Wu X | title = Immunogenicity and therapeutic effects of Ag85A/B chimeric DNA vaccine in mice infected with Mycobacterium tuberculosis | journal = FEMS Immunology and Medical Microbiology | volume = 66 | issue = 3 | pages = 419–426 | date = December 2012 | pmid = 23163873 | doi = 10.1111/1574-695X.12008 | doi-access = free }} The safety and immunogenicity of this construct was tested in animal models. This construct can be easily transformed into the construct that encodes S-protein of SARS-CoV-2. In Russia, State Research Center of Virology and Biotechnology VECTOR is in developing stage of vaccine against COVID-19 using Moscow strain of Sendai virus as a vector backbone.

In Japan researchers have developed two intranasal vaccine candidates against SARS-CoV-2. One design utilizes a modified Sendai virus (SeV) as a vector to deliver the SARS-CoV-2 spike protein's receptor binding domain (RBD) directly to the respiratory tract. In pre-clinical studies, mice received the vaccine intranasally. Mice demonstrated elevated levels of antibodies specific to the SARS-CoV-2 S-RBD (IgM, IgG, IgA) in both their blood serum and bronchoalveolar lavage fluid, lasting up to 12 weeks. Another design uses a similar F-gene lacking SeV vector but different SARS-CoV-2 antigens. Instead of the S-protein, the vaccine design used SARS-CoV-2 nucleocapsid (N), membrane (M), and envelope (E) proteins as immunogens. The study found strong CD8+ T cell responses against these antigens, suggesting intranasal vaccination can trigger immune cells (CD8+ T cells) that target the virus and help control SARS-CoV-2 infection. Vaccination significantly reduced viral load in nasopharyngeal swabs of macaques on day 2 post-challenge, compared to the unvaccinated control group.{{cite journal | vauthors = Ishii H, Nomura T, Yamamoto H, Nishizawa M, Thu Hau TT, Harada S, Seki S, Nakamura-Hoshi M, Okazaki M, Daigen S, Kawana-Tachikawa A, Nagata N, Iwata-Yoshikawa N, Shiwa N, Suzuki T, Park ES, Ken M, Onodera T, Takahashi Y, Kusano K, Shimazaki R, Suzaki Y, Ami Y, Matano T | title = Neutralizing-antibody-independent SARS-CoV-2 control correlated with intranasal-vaccine-induced CD8⁺ T cell responses | journal = Cell Reports. Medicine | volume = 3 | issue = 2 | pages = 100520 | date = February 2022 | pmid = 35233545 | pmc = 8768424 | doi = 10.1016/j.xcrm.2022.100520 }}

alt=Schematic representation of [[virion|thumb|Schematic representation of virion]]

Virion structure is well described in a published review. Sendai virus is an enveloped virus: its outer layer is a lipid envelope, which contains glycoprotein hemagglutinin-neurominidase (HN){{Cite journal |url=https://www.uniprot.org/uniprot/P04853 |title=HN - Hemagglutinin-neuraminidase - Sendai virus (strain Z) (SeV) - HN gene & protein |website=www.uniprot.org |access-date=2019-08-09}} with two enzymatic activities (hemagglutinating and neuraminidase).{{cite journal |vauthors=Scheid A, Choppin PW |title=Identification of biological activities of paramyxovirus glycoproteins. Activation of cell fusion, hemolysis, and infectivity of proteolytic cleavage of an inactive precursor protein of Sendai virus |journal=Virology |volume=57 |issue=2 |pages=475–90 |date=February 1974 |pmid=4361457 |doi=10.1016/0042-6822(74)90187-1}} Hemagglutinin (H) serves as a cell attachment factor and membrane fusion protein. Neuraminidase (NA) is a sialidase that cleaves and removes sialic acid from the surface of a host cell. This cleavage promotes the fusion of the viral lipid envelope with the cell outer membrane.

In the lipid envelope of the virus located also a fusion protein (F),{{Cite web |url=https://www.uniprot.org/uniprot/P04855 |title=F - Fusion glycoprotein F0 precursor - Sendai virus (strain Z) (SeV) - F gene & protein |website=www.uniprot.org |access-date=2019-08-09}} which is also a glycoprotein that ensures the virus entry into a host cell after viral adsorption. F-protein, as other paramyxoviral fusion proteins, is a trimeric class I viral membrane fusion protein. It is produced in the form of an F0 precursor that must be cleaved by host cell proteases into disulfide-bonded F1 and F2 subunits in order for the trimer to become biologically active. Under the lipid membrane is a matrix protein (M);{{Cite web |url=https://www.uniprot.org/uniprot/O57299 |title=M - Matrix protein - Sendai virus (strain Ohita) (SeV) - M gene & protein |website=www.uniprot.org |access-date=2019-08-09}} it forms the inner layer of the virus envelope and stabilizes it structure. The SeV virion also contains the nucleocapsid core, which is composed of the genomic RNA, the nucleocapsid protein (NP),{{Cite web |url=https://www.uniprot.org/uniprot/P04858 |title=N - Nucleoprotein - Sendai virus (strain Z) (SeV) - N gene & protein |website=www.uniprot.org |access-date=2019-08-09}} the phosphoproteins (P),{{Cite web |url=https://www.uniprot.org/uniprot/P04859 |title=P/V/C - Phosphoprotein - Sendai virus (strain Harris) (SeV) - P/V/C gene & protein |website=www.uniprot.org |access-date=2019-08-09}} which is an essential subunit of the viral of RNA-dependent RNA polymerase (RDRP), and the large protein (L){{Cite web |url=https://www.uniprot.org/uniprot/P06829 |title=L - RNA-directed RNA polymerase L - Sendai virus (strain Enders) (SeV) - L gene & protein |website=www.uniprot.org |access-date=2019-08-09}} that is a catalytic subunit of this polymerase. C-protein, which is translated from an alternative reading frame of the P-coding mRNA, is also associated with a viral capsid.{{cite journal |vauthors=Yamada H, Hayata S, Omata-Yamada T, Taira H, Mizumoto K, Iwasaki K |title=Association of the Sendai virus C protein with nucleocapsids |journal=Archives of Virology |volume=113 |issue=3–4 |pages=245–53 |date=1990 |pmid=2171459 |doi=10.1007/bf01316677 |s2cid=24592567}} It is present in SeV virions at relatively low levels (40 molecules/genome).

File:CGT-12-410 F2.jpg

[[File:Genome structure.tif|alt=|thumb|Genome structure

The positions of translation initiation sites for products of the alternative reading frame of the P-coding mRNA]]

The SeV genome is non-segmented, negative-sense RNA, of about 15.384 n. in length, and contains the noncoding 3’ leader and 5’ trailer regions, which are about 50 nucleotides in length.{{cite journal |vauthors=Sakai Y, Kiyotani K, Fukumura M, Asakawa M, Kato A, Shioda T, Yoshida T, Tanaka A, Hasegawa M, Nagai Y |title=Accommodation of foreign genes into the Sendai virus genome: sizes of inserted genes and viral replication |journal=FEBS Letters |volume=456 |issue=2 |pages=221–6 |date=August 1999 |pmid=10456313 |doi=10.1016/s0014-5793(99)00960-6 |s2cid=1285541|doi-access=free |bibcode=1999FEBSL.456..221S }} As in other respiroviruses from family Paramyxoviridae, in SeV they work as cis-acting elements essential for replication. A 3’ leader sequence acts as a transcriptional promoter. Between these non-coding regions are located six genes, which encode the nucleocapsid (NP) protein, phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin-neuraminidase (HN) and large (L) protein in this order from the 3’ terminus. The RNA-dependent RNA polymerase of the SeV consists of the large protein (L) and the phosphoprotein (P). The structural gene sequence of SeV is as follows: 3′-NP-P-M-F-HN-L-5′. Intergenomic regions between these genes are three nucleotides long as in other respiroviruses. Additional proteins, which are frequently called non structural or accessory proteins can be produced from the P gene, using alternative reading frames.{{cite journal |vauthors=Curran J, Kolakofsky D |title=Ribosomal initiation from an ACG codon in the Sendai virus P/C mRNA |journal=The EMBO Journal |volume=7 |issue=1 |pages=245–51 |date=January 1988 |pmid=2834203 |pmc=454264 |doi=10.1002/j.1460-2075.1988.tb02806.x}} The Sendai virus P/C mRNA contains five ribosomal initiation sites between positions 81 and 201 from the 5' end. One of these sites initiates in the P open reading frame, whereas four others initiate a nested set of C proteins (C', C, Y1, Y2).{{cite journal |vauthors=Dillon PJ, Gupta KC |title=Expression of five proteins from the Sendai virus P/C mRNA in infected cells |journal=Journal of Virology |volume=63 |issue=2 |pages=974–7 |date=February 1989 |pmid=2536120 |pmc=247778 |doi=10.1128/JVI.63.2.974-977.1989}}{{cite journal |vauthors=de Breyne S, Simonet V, Pelet T, Curran J |title=Identification of a cis-acting element required for shunt-mediated translational initiation of the Sendai virus Y proteins |journal=Nucleic Acids Research |volume=31 |issue=2 |pages=608–18 |date=January 2003 |pmid=12527769 |pmc=140508 |doi=10.1093/nar/gkg143}} These C proteins are initiated in the + 1 reading frame to that of P at different translation starting sites. Sendai virus uses ribosome shunting to express Y1 and Y2 proteins that initiate at the fourth and fifth start sites on the P/C mRNA (respectively). Three additional SeV proteins are also encoded by P/C mRNA. Two of these proteins V and W are products of RNA editing, at codon 317 of the mRNA - G residues are added co-transcriptionally, (+one G residue for V and +two G for W).{{cite journal |vauthors=Garcin D, Curran J, Itoh M, Kolakofsky D |title=Longer and shorter forms of Sendai virus C proteins play different roles in modulating the cellular antiviral response |journal=Journal of Virology |volume=75 |issue=15 |pages=6800–7 |date=August 2001 |pmid=11435558 |pmc=114406 |doi=10.1128/JVI.75.15.6800-6807.2001}} The third - X protein is represented by 95 amino acids of the C terminal of the P protein and independently initiated by ribosomes.{{cite journal |vauthors=Curran J, Kolakofsky D |title=Scanning independent ribosomal initiation of the Sendai virus X protein |journal=The EMBO Journal |volume=7 |issue=9 |pages=2869–74 |date=September 1988 |pmid=2846286 |pmc=457080 |doi=10.1002/j.1460-2075.1988.tb03143.x}} All these non-structural proteins have several functions, including the organization of viral RNA synthesis and helping the virus to infect rodent cells by escaping host innate immunity (see "The mechanism of viral immunosuppression in natural hosts" section above). It has also been found that C protein facilitates budding of virus-like particles{{cite journal |vauthors=Irie T, Nagata N, Yoshida T, Sakaguchi T |title=Recruitment of Alix/AIP1 to the plasma membrane by Sendai virus C protein facilitates budding of virus-like particles |journal=Virology |volume=371 |issue=1 |pages=108–20 |date=February 2008 |pmid=18028977 |doi=10.1016/j.virol.2007.09.020|doi-access=free }} and small amounts of C protein are associated with a viral capsid.

The genomes of non segmented negative-stranded RNA viruses (including paramyxoviruses) have a low rate of homologous recombination and evolve comparatively slowly.{{cite journal | vauthors = Chare ER, Gould EA, Holmes EC | title = Phylogenetic analysis reveals a low rate of homologous recombination in negative-sense RNA viruses | journal = The Journal of General Virology | volume = 84 | issue = Pt 10 | pages = 2691–2703 | date = October 2003 | pmid = 13679603 | doi = 10.1099/vir.0.19277-0 | doi-access = free }}{{cite journal | vauthors = Han GZ, Worobey M | title = Homologous recombination in negative sense RNA viruses | journal = Viruses | volume = 3 | issue = 8 | pages = 1358–1373 | date = August 2011 | pmid = 21994784 | pmc = 3185808 | doi = 10.3390/v3081358 | doi-access = free }} Multiple reasons for this genomic stability likely exist: (1) the genomes of these viruses are nonsegmented, therefore cannot undergo genetic reassortment, (2) each protein and each amino acid has an important function. Therefore, any new genetic insertion, substitution or deletion would lead to a decrease or total loss of function that would in turn cause the new virus variant to be less viable. (3) Sendai virus belong to viruses that are governed by the “rule of six”. SeV genome as genomes of other paramyxoviruses mainly include six genes, which encode for six major proteins.{{cite journal | vauthors = Kolakofsky D, Roux L, Garcin D, Ruigrok RW | title = Paramyxovirus mRNA editing, the "rule of six" and error catastrophe: a hypothesis | journal = The Journal of General Virology | volume = 86 | issue = Pt 7 | pages = 1869–1877 | date = July 2005 | pmid = 15958664 | doi = 10.1099/vir.0.80986-0 | doi-access = free }} Low rate of homologous RNA recombination in paramyxoviruses probably results from this unusual genomic requirement for polyhexameric length (6n+0). Natural high genomic stability of SeV is a positive feature for it potential use as a vaccine vector or as an oncolytic agent. For any clinical or industrial applications, it is important that SeV genomic and inserted foreign trans genes would be expressed in a stable way. Paramyxoviruses show relatively little genomic or antigenic change over time. They are known to stably express a wide variety of heterologous antigens at relatively high levels in many species of animals.{{Citation | vauthors = Englund JA, Moscona A |title=Paramyxoviruses: Parainfluenza Viruses |date=2014 |work=Viral Infections of Humans |pages=579–600 | veditors = Kaslow RA, Stanberry LR, Le Duc JW |place=Boston, MA |publisher=Springer US |language=en |doi=10.1007/978-1-4899-7448-8_25 |isbn=978-1-4899-7447-1 }}{{Citation | vauthors = Samal SK |title=Paramyxoviruses as Vaccine Vectors |date=2021 |work=Viral Vectors in Veterinary Vaccine Development |pages=113–139 | veditors = Vanniasinkam T, Tikoo SK, Samal SK |url=https://link.springer.com/10.1007/978-3-030-51927-8_8 |access-date=2024-05-26 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-51927-8_8 |isbn=978-3-030-51926-1 |url-access=subscription }}{{cite journal | vauthors = Ikegame S, Beaty SM, Stevens C, Won T, Park A, Sachs D, Hong P, Lee B, Thibault PA | title = Genome-wide transposon mutagenesis of paramyxoviruses reveals constraints on genomic plasticity | journal = PLOS Pathogens | volume = 16 | issue = 10 | pages = e1008877 | date = October 2020 | pmid = 33035269 | pmc = 7577504 | doi = 10.1371/journal.ppat.1008877 | doi-access = free | veditors = Lowen AC }}

The SeV F protein is a type I membrane glycoprotein that is synthesized as an inactive precursor (F₀) that must be activated by proteolytic cleavage at residue arginine-116. After the cleavage F₀ precursor yields two disulfide-linked subunits F₁ and F₂.{{cite journal |vauthors=Portner A, Scroggs RA, Naeve CW |title=The fusion glycoprotein of Sendai virus: sequence analysis of an epitope involved in fusion and virus neutralization |journal=Virology |volume=157 |issue=2 |pages=556–9 |date=April 1987 |pmid=2435061 |doi=10.1016/0042-6822(87)90301-1}} Paramyxoviruses use different host cell proteases to activate their F-proteins. Sendai virus uses activating proteases that are serine endopeptidases represented by tryptase beta 2-(TPSB2),[https://www.wikigenes.org/e/gene/e/29268.html WikiGenes - Collaborative Publishing] (which has aliases such as tryptase II, tryptase Clara, club cells tryptase, mast cells tryptase,{{cite journal |vauthors=Payne V, Kam PC |title=Mast cell tryptase: a review of its physiology and clinical significance |journal=Anaesthesia |volume=59 |issue=7 |pages=695–703 |date=July 2004 |pmid=15200544 |doi=10.1111/j.1365-2044.2004.03757.x |s2cid=7611291 | doi-access = free}}{{cite journal |vauthors=Chen Y, Shiota M, Ohuchi M, Towatari T, Tashiro J, Murakami M, Yano M, Yang B, Kido H |title=Mast cell tryptase from pig lungs triggers infection by pneumotropic Sendai and influenza A viruses. Purification and characterization |journal=European Journal of Biochemistry |volume=267 |issue=11 |pages=3189–97 |date=June 2000 |pmid=10824103 |doi=10.1046/j.1432-1327.2000.01346.x | doi-access = free}}{{cite journal |vauthors=Tashiro M, Yokogoshi Y, Tobita K, Seto JT, Rott R, Kido H |title=Tryptase Clara, an activating protease for Sendai virus in rat lungs, is involved in pneumopathogenicity |journal=Journal of Virology |volume=66 |issue=12 |pages=7211–6 |date=December 1992 |pmid=1331518 |pmc=240423 |doi=10.1128/JVI.66.12.7211-7216.1992}}{{cite journal |vauthors=Kido H, Niwa Y, Beppu Y, Towatari T |title=Cellular proteases involved in the pathogenicity of enveloped animal viruses, human immunodeficiency virus, influenza virus A and Sendai virus |journal=Advances in Enzyme Regulation |volume=36 |pages=325–47 |date=1996 |pmid=8869754 |doi=10.1016/0065-2571(95)00016-X}}) trypsin 1 (PRSS1),{{cite journal |vauthors=Le TQ, Kawachi M, Yamada H, Shiota M, Okumura Y, Kido H |title=Identification of trypsin I as a candidate for influenza A virus and Sendai virus envelope glycoprotein processing protease in rat brain |journal=Biological Chemistry |volume=387 |issue=4 |pages=467–75 |date=April 2006 |pmid=16606346 |doi=10.1515/BC.2006.062 |s2cid=11969821 }} mini-plasmin (PLG){{cite journal |vauthors=Murakami M, Towatari T, Ohuchi M, Shiota M, Akao M, Okumura Y, Parry MA, Kido H |title=Mini-plasmin found in the epithelial cells of bronchioles triggers infection by broad-spectrum influenza A viruses and Sendai virus |journal=European Journal of Biochemistry |volume=268 |issue=10 |pages=2847–55 |date=May 2001 |pmid=11358500 |doi=10.1046/j.1432-1327.2001.02166.x | doi-access = free}} and transmembrane serine protease 2 (TMPRSS2).{{cite journal |vauthors=Abe M, Tahara M, Sakai K, Yamaguchi H, Kanou K, Shirato K, Kawase M, Noda M, Kimura H, Matsuyama S, Fukuhara H, Mizuta K, Maenaka K, Ami Y, Esumi M, Kato A, Takeda M |title=TMPRSS2 is an activating protease for respiratory parainfluenza viruses |journal=Journal of Virology |volume=87 |issue=21 |pages=11930–5 |date=November 2013 |pmid=23966399 |pmc=3807344 |doi=10.1128/JVI.01490-13}} Most likely, blood clotting factor X (F10) is capable to cleave and activate SeV F₀.{{cite journal |vauthors=Gotoh B, Ogasawara T, Toyoda T, Inocencio NM, Hamaguchi M, Nagai Y |title=An endoprotease homologous to the blood clotting factor X as a determinant of viral tropism in chick embryo |journal=The EMBO Journal |volume=9 |issue=12 |pages=4189–95 |date=December 1990 |pmid=2174359 |pmc=552195 |doi=10.1002/j.1460-2075.1990.tb07643.x}}{{cite journal |vauthors=Ogasawara T, Gotoh B, Suzuki H, Asaka J, Shimokata K, Rott R, Nagai Y |title=Expression of factor X and its significance for the determination of paramyxovirus tropism in the chick embryo |journal=The EMBO Journal |volume=11 |issue=2 |pages=467–72 |date=February 1992 |pmid=1371460 |pmc=556476 |doi=10.1002/j.1460-2075.1992.tb05076.x}}{{cite journal |vauthors=Gotoh B, Yamauchi F, Ogasawara T, Nagai Y |title=Isolation of factor Xa from chick embryo as the amniotic endoprotease responsible for paramyxovirus activation |journal=FEBS Letters |volume=296 |issue=3 |pages=274–8 |date=January 1992 |pmid=1537403 |doi=10.1016/0014-5793(92)80303-x |s2cid=33852517 | doi-access = free|bibcode=1992FEBSL.296..274G }} It is possible that other, not yet identified cellular proteases, can also process the F₀ protein of SeV.

File:Sendai virus receptors.tif

To infect host cells SeV must first bind to cell surface receptors using its hemagglutinin-neuraminidase (HN) protein. The receptor-virus attaching process triggers a conformational change in HN, which allosterically promotes the viral fusion (F) protein to promote virus envelope - cell membrane fusion. The receptor attachment is cooperative with respect to receptor density. SeV cell entry receptors are represented mainly by glycoproteins and glycolipids.{{cite journal | vauthors = Matveeva OV, Shabalina SA | title = Prospects for Using Expression Patterns of Paramyxovirus Receptors as Biomarkers for Oncolytic Virotherapy | journal = Cancers | volume = 12 | issue = 12 | pages = 3659 | date = December 2020 | pmid = 33291506 | pmc = 7762160 | doi = 10.3390/cancers12123659 | doi-access = free }} The table below lists all the molecules that have been shown to function as SeV receptors. Human sialoglycoprotein - cluster of differentiation (CD 235a) is an example of glycoproteins that facilitates SeV cell entry. However, other type of proteins that are not glycoproteins also can assist SeV to penetrate cells. Thus, C-type lectin represented by asialoglycoprotein receptor (ASGP-R), ASGR1{{Cite web | work = The Human Protein Atlas |date=February 4, 2023 |title=Asialoglycoprotein receptor 1 expression |url=https://www.proteinatlas.org/ENSG00000141505-ASGR1 |access-date=February 4, 2023 }}) has been shown to be able to function as a SeV cell entry receptor. Among glycosphingolipids two types of glycans are serving as SeV receptors. The first type is represented by fucosylated glycans and the second one by sialylated glycans. The number, positioning, and chemical linkage of sialic acid-containing receptors can be an important determinant of the strength and efficiency of viral attachment, which can play an important role both in host and tissue tropism.

The expression of molecules that can facilitate SeV cell entry, frequently accelerates carcinogenesis and/or metastasis development. The asialoglycoprotein receptor is highly expressed in liver cancers. The presence of Sialyl-Lewis^x antigen (cluster of differentiation 15s (CD15s)), which is a fucosylated glycan, on the outer cell membrane, correlates with invasion potential of malignant cells, tumor recurrence, and overall patient survival for an extremely wide range of cancers. Expression of the Vim2 antigen, which is another SeV cell entry receptor represented by fucosylated glycan, is very important for the extravascular infiltration process of acute myeloid leukemia cells. Metastatic cancer cells often are coated with glycolipids that are rich in sialic acids. SeV binds to α2,3-linked sialic acid containing glycolipids. For example, GD1a, which is a ganglioside and sialylated glycan (glycolipid), is found in large quantities on the surfaces of breast cancer stem cells. High cell surface expression of another SeV receptor - ganglioside sialosylparagloboside /SPG/ NeuAcα2-3PG. characterizes lymphoid leukemia cells. Among other receptors represented by gangliosides GT1b is highly expressed on the outer membranes of brain metastases cells that originate from an extremely broad range of cancer, while GD1a, GT1b and GQ1b can be detected in human gliosarcomas. However, their quantity is not exceeding the quantity in normal frontal cerebral cortex.

File:MV life cycle.tif

A fluorescence microscopy-based assay reveals that the relative number of SeV virions bound to the receptor can be defined as 0.5 for GM3, as 1 for GD1a, and as 2 for Gq1b. The structures of some of these receptors are available for visualization through SugarBindDB - a resource of glycan-mediated host–pathogen interactions.{{cite book |title=Glycoscience: Biology and Medicine |vauthors=Mariethoz J, Khatib K, Campbell MP, Packer NH, Mullen E, Lisacek F |chapter=SugarBindDB: Resource of Pathogen Lectin-Glycan Interactions |date=2014-10-20 |publisher=Springer Japan |isbn=9784431548409 |pages=275–282 |doi=10.1007/978-4-431-54841-6_28}} Others are available through KEGG Glycan Database,{{Cite web |title=DBGET search - GLYCAN |url=https://www.genome.jp/dbget-bin/www_bfind?glycan |access-date=2019-08-15 |website=www.genome.jp}} PubChem compound database,{{Cite web |title=About PubChem |url=https://pubchemdocs.ncbi.nlm.nih.gov/about |access-date=2019-08-15 |website=pubchemdocs.ncbi.nlm.nih.gov}} and TOXNET database (toxicology data network) of US National Library of Medicine.{{Cite web |title=TOXNET |url=https://toxnet.nlm.nih.gov/ |access-date=2019-08-15 |website=toxnet.nlm.nih.gov}}

File:SeV cell entry seven stages.jpg fusion mechanism of viral and cell plasma membrane]]

Because SeV is a negative-strand RNA virus the virus entire life cycle is completed in the cytoplasm using its own RNA polymerase.

File:Viruses-12-00161-g006.jpg

Sendai virus initiates infection process by host cell adsorption mediated by the recognition of specific receptor molecules. Hemagglutinin neuraminidase (HN) serves as a virus cell attachment protein that interacts with a specific cell entry receptor. NH has sialidase activity, and it is capable of cleaving sialic acid residues from the cell receptor. This cleavage triggers the fusion process of viral envelope and cell membrane, which promotes by cooperation of NH with the viral fusion protein (F).{{cite journal |vauthors=Chang A, Dutch RE |title=Paramyxovirus fusion and entry: multiple paths to a common end |journal=Viruses |volume=4 |issue=4 |pages=613–36 |date=April 2012 |pmid=22590688 |pmc=3347325 |doi=10.3390/v4040613 | doi-access = free}} The SeV F-protein as other Paramyxovirus structural fusion proteins is a trimeric molecule that belongs to class I viral membrane fusion proteins.{{cite journal | vauthors = Azarm KD, Lee B | title = Differential Features of Fusion Activation within the Paramyxoviridae | journal = Viruses | volume = 12 | issue = 2 | pages = 161 | date = January 2020 | pmid = 32019182 | pmc = 7077268 | doi = 10.3390/v12020161 | doi-access = free }} To perform the fusion function F protein must be proteolytically activated from it precursor inactive form F₀.{{cite journal |vauthors=Lamb RA, Jardetzky TS |title=Structural basis of viral invasion: lessons from paramyxovirus F |journal=Current Opinion in Structural Biology |volume=17 |issue=4 |pages=427–36 |date=August 2007 |pmid=17870467 |pmc=2086805 |doi=10.1016/j.sbi.2007.08.016}} This activation requires F₀ cleavage by host serine protease before the virus adsorption (see the section “proteolytic cleavage by cellular proteases”). F₀ must be cleaved by the host protease into F1 and F2 subunits that remained connected through a disulfide covalent bond. The cleavage site in the F₀-protein is located N-terminal to the fusion peptide which has N-terminal Hepta-Repeat 1 (HR1) and C-terminal Hepta-Repeat 2 (HR2) domains. The illustration below shows 5 stages of the fusion of the virus envelope and cellular host membrane. 1) The pre-fusion, F protein (highlighted in red) is protruding from the lipid bilayer of the viral envelope and is in a close proximity to the cellular membrane. 2) Receptor-HN binding, during the SeV host cell attachment process, triggers the release of the fusion peptide from the F-protein. The peptide inserts itself into the host cell membrane. This insertion is accompanied by the transformation of the HR1 domain from a helical structure to an extended helical trimeric coil-coil structure. 3) Transformed HR1 domain attaches viral F-protein to the host-cell membrane. 4) Two lipid bilayers (viral and cellular) fuse with each other. 5) The fusion of the HR2 and HR1 domains of the F-protein promotes the establishment of a stable six-helix bundle structure (6HB). The formation of the 6HB structure leads to the establishment of the pore and the completion of the fusion process. Viral genomic material enters the host cell through this formed pore.

After a merging of the host membrane and the viral envelope, the SeV according to one model is “[https://www.rsc.org/publishing/journals/prospect/ontology.asp?id=GO:0019061&MSID=b810306b uncoating]” with diffusion of the viral envelope proteins into the host plasma membrane.{{cite journal |vauthors=Haywood AM |title=Membrane uncoating of intact enveloped viruses |journal=Journal of Virology |volume=84 |issue=21 |pages=10946–55 |date=November 2010 |pmid=20668081 |pmc=2953184 |doi=10.1128/JVI.00229-10}} According to another model the virus did not release its envelope proteins into the host membrane. The viral and host membranes are fused and a connecting structure is made. This connecting structure serves as a transportation "highway" for the viral ribonucleoprotein (RNP). Thus, RNP travels through the connecting structure to reach the cell interior allowing SeV genetic material to enter the host cell cytoplasm.{{cite journal |vauthors=Jardetzky TS, Lamb RA |title=Activation of paramyxovirus membrane fusion and virus entry |journal=Current Opinion in Virology |volume=5 |pages=24–33 |date=April 2014 |pmid=24530984 |pmc=4028362 |doi=10.1016/j.coviro.2014.01.005}}

Once in the cytoplasm, the SeV genomic RNA is getting involved, as a template, in two different RNA synthetic processes performed by RNA-dependent RNA polymerase, which consists of L and P proteins: (1) transcription to generate mRNAs and (2) replication to produce a positive-sense antigenome RNA that in turn acts as a template for production of progeny negative-strand genomes.{{cite book |vauthors=Whelan SP, Barr JN, Wertz GW |title=Biology of Negative Strand RNA Viruses: The Power of Reverse Genetics |chapter=Transcription and Replication of Nonsegmented Negative-Strand RNA Viruses |series=Current Topics in Microbiology and Immunology |volume=283 |pages=61–119 |date=2004 |location=Berlin, Heidelberg | publisher = Springer |pmid=15298168 |doi=10.1007/978-3-662-06099-5_3 |isbn=978-3-642-07375-5}}{{cite journal |vauthors=Noton SL, Fearns R |title=Initiation and regulation of paramyxovirus transcription and replication |journal=Virology |volume=479 |pages=545–354 |date=May 2015 |pmid=25683441 |pmc=4424093 |doi=10.1016/j.virol.2015.01.014}} RNA-dependent RNA polymerase promotes the generation of mRNAs methylated cap structures.{{cite journal |vauthors=Ogino T, Kobayashi M, Iwama M, Mizumoto K |title=Sendai virus RNA-dependent RNA polymerase L protein catalyzes cap methylation of virus-specific mRNA |journal=The Journal of Biological Chemistry |volume=280 |issue=6 |pages=4429–35 |date=February 2005 |pmid=15574411 |doi=10.1074/jbc.M411167200 |s2cid=27655763 | doi-access = free}}

The NP protein is thought to have both structural and functional roles{{cite journal |vauthors=Myers TM, Moyer SA |title=An amino-terminal domain of the Sendai virus nucleocapsid protein is required for template function in viral RNA synthesis |journal=Journal of Virology |volume=71 |issue=2 |pages=918–24 |date=February 1997 |pmid=8995608 |pmc=191139 |doi=10.1128/JVI.71.2.918-924.1997}} This protein concentration is believed to regulate the switch from RNA transcription to RNA replication. The genomic RNA functions as the template for the viral RNA transcription until the NP protein concentration increases. As the NP protein accumulates, the transition from the transcription to the replication occurs.{{cite book | vauthors = Ryu SW |chapter=Other Negative-Strand RNA Viruses |date=2017 |pages=213–224 |publisher=Elsevier |isbn=978-0-12-800838-6 |doi=10.1016/b978-0-12-800838-6.00016-3 |title=Molecular Virology of Human Pathogenic Viruses |s2cid=88812845}} The NP protein encapsidates the genomic RNA, forming a helical nucleocapsid which is the template for RNA synthesis by the viral RNA polymerase. The protein is a crucial component of the following complexes NP-P (P, phosphoprotein), NP-NP, nucleocapsid-polymerase, and RNA-NP. All these complexes are needed for the viral RNA replication. Research has demonstrated that de novo synthesis of the NP and P proteins is essential for efficient viral transcription. Studies using SeV mutants deficient in NP or P proteins, with genome replication disabled, revealed that the P protein is necessary for viral gene expression. Furthermore, the NP protein plays a crucial role in enhancing primary transcription. Without newly synthesized NP protein, early transcription occurs at minimal levels, while its presence restores normal transcriptional activity. These findings indicate that the synthesis of these proteins facilitates the transition from preliminary to efficient transcription, underscoring their importance in the viral life cycle.{{Cite journal |last1=Wiegand |first1=Marian A. |last2=Bossow |first2=Sascha |last3=Schlecht |first3=Sabine |last4=Neubert |first4=Wolfgang J. |date=2007-12-15 |title=De Novo Synthesis of N and P Proteins as a Key Step in Sendai Virus Gene Expression |url=https://doi.org/10.1128/jvi.00914-07 |journal=Journal of Virology |volume=81 |issue=24 |pages=13835–13844 |doi=10.1128/jvi.00914-07 |pmid=17855540 |issn=0022-538X|pmc=2168830 }}

Two different sets of proteins are translated from viral mRNAs. The first set is represented by six structural proteins that include nucleocapsid protein (NP), phosphoprotein (P), matrix protein (M), fusion protein (F), neuraminidase (NA) and large protein (L). All these proteins have variable functions and are incorporated into the viral capsid (see the section “virion structure” above). The second set is represented by seven non structural or accessory proteins. These proteins are translated from the polycistronic mRNA of P gene. This mRNA encodes eight translation products, and P-protein is only one of them. Alternative variants of translation are represented by V,W, C, C’,Y,Y’ and X proteins. The proteins C’, C, Y1, Y2 are products of mRNA alternative reading frame, they collectively referred as C-proteins or C-nested proteins and they share common C-terminal end.{{cite journal |vauthors=Latorre P, Kolakofsky D, Curran J |title=Sendai virus Y proteins are initiated by a ribosomal shunt |journal=Molecular and Cellular Biology |volume=18 |issue=9 |pages=5021–31 |date=September 1998 |pmid=9710586 |pmc=109087 |doi=10.1128/mcb.18.9.5021}} The X protein also shares the same C-terminal end and its translation also independently initiated by ribosomes. The proteins V and W are products of cotranscriptional mRNA editing. All these non-structural proteins have multiple functions, including the organization of viral RNA synthesis and helping the virus to infect host cells by escaping host innate immunity (see "The mechanism of viral immunosuppression in natural hosts" section above).

File:HN and P and M proteins 3.tif model depicting formation of the viral assembly complex]]

After translation, SeV nucleocapsids (RNP complex) assemble, and move using microtubules network through intracellular vesicular trafficking pathway.{{cite journal | vauthors = Chambers R, Takimoto T | title = Trafficking of Sendai virus nucleocapsids is mediated by intracellular vesicles | journal = PLOS ONE | volume = 5 | issue = 6 | pages = e10994 | date = June 2010 | pmid = 20543880 | pmc = 2881874 | doi = 10.1371/journal.pone.0010994 | bibcode = 2010PLoSO...510994C | doi-access = free }} In preparation for the budding process, three viral lipophilic proteins HN, F and M migrate through the secretory pathway to a host cell membrane.{{cite journal | vauthors = Harrison MS, Sakaguchi T, Schmitt AP | title = Paramyxovirus assembly and budding: building particles that transmit infections | journal = The International Journal of Biochemistry & Cell Biology | volume = 42 | issue = 9 | pages = 1416–1429 | date = September 2010 | pmid = 20398786 | pmc = 2910131 | doi = 10.1016/j.biocel.2010.04.005 }} It is assumed that the interaction of these three proteins with each other is needed for their migration to cellular budding sites. The binding of lipophilic protein complex to the host membrane facilitates the interaction of this three protein complex with the SeV nucleocapsid. It has been shown that for efficient virion production SeV induces the β-cytoplasmic actin remodeling in its host cell.{{cite journal | vauthors = Miazza V, Mottet-Osman G, Startchick S, Chaponnier C, Roux L | title = Sendai virus induced cytoplasmic actin remodeling correlates with efficient virus particle production | journal = Virology | volume = 410 | issue = 1 | pages = 7–16 | date = February 2011 | pmid = 21075412 | doi = 10.1016/j.virol.2010.10.003 | doi-access = free }}

Two of SeV proteins: HA and F, after their binding directly to a cellular membrane, promote a cell-cell fusion, which leads to a large multinuclear cell formation (syncytium). This formation involves the fusion of infected cells with adjacent target cells and remains an important mechanism of direct cell-to-cell spread of viral components. Thus, a SeV infection in a form of genetic material in partially assembled virions can spread without any exposure to host neutralizing antibodies (see the section "Directed cells fusion (syncytium formation)" for details and references).

Sendai virus, as all other envelope viruses, uses host cellular membrane lipid bilayer for viral capsid membrane formation. Binding to a host cell membrane of viral proteins (M, HN and F) promotes their interaction with RNP complex, which is composed of the viral genomic RNA bound to SeV proteins (NP, P and L). Thus, all viral structural components, including viral glycoproteins and genomic RNP complex, are getting assembled together. After such assembling the infectious viral particles are budding out from individually or collectively infected cells (syncitia). It has been suggested that recirculating endosomes are involved in viral RNP complex translocation. C-protein facilitates budding by interacting with AIP1/Alix, which is a host protein that is involved in apoptosis and endosomal membrane trafficking. The infectious virus particles usually released by 24 hours post infection (hpi), and peak titers appeared between 48 and 72 hpi.

Sendai virus can establish persistent infection in its host cells. Multiple rounds of virus subculturing result in a creation of new virus variants with high ability to establish persistent infection. These SeV variants develop certain genotypic changes.{{cite journal | vauthors = Ito M, Takeuchi T, Nishio M, Kawano M, Komada H, Tsurudome M, Ito Y | title = Early stage of establishment of persistent Sendai virus infection: unstable dynamic phase and then selection of viruses which are tightly cell associated, temperature sensitive, and capable of establishing persistent infection | journal = Journal of Virology | volume = 78 | issue = 21 | pages = 11939–11951 | date = November 2004 | pmid = 15479834 | pmc = 523293 | doi = 10.1128/JVI.78.21.11939-11951.2004 }} Specific amino acid substitutions accumulated in the M protein and the L protein were show to be associated with persistent infection in mouse connective tissue cells (L-929) and hamster kidney fibroblasts (BHK-21). It has been shown that 4-5 point mutations might distinguish Sendai variants capable of persistent infections from those that are incapable.The most common single nucleotide mutations are found in the leader sequence (position 16) and in the following genes: the M gene (position 850), the F gene (position 782), and the L gene (positions 832 and 1743).{{Cite journal | vauthors = Iwata M, Kawabata R, Morimoto N, Takeuchi RF, Sakaguchi T, Irie T, Osakada F |date=2024-04-02 |title=Evolutionary engineering and characterization of Sendai virus mutants capable of persistent infection and autonomous production |journal=Frontiers in Virology |volume=4 |doi=10.3389/fviro.2024.1363092 |doi-access=free |issn=2673-818X}}

The persistent infection can also be established instantly in interferon regulatory factor 3 (IRF-3)-knockdown cells. IRF-3 is a key proapoptotic protein that after activation by SeV triggers apoptosis. IRF-3-knockdown cells express viral protein and produces low levels of infectious virions.{{cite journal | vauthors = Coakley C, Peter C, Fabry S, Chattopadhyay S | title = Establishment of a Human Cell Line Persistently Infected with Sendai Virus | journal = Bio-Protocol | volume = 7 | issue = 16 | pages = e2512 | date = August 2017 | pmid = 34541174 | doi = 10.21769/BioProtoc.2512 | pmc = 8413619 }}{{cite journal | vauthors = Chattopadhyay S, Fensterl V, Zhang Y, Veleeparambil M, Yamashita M, Sen GC | title = Role of interferon regulatory factor 3-mediated apoptosis in the establishment and maintenance of persistent infection by Sendai virus | journal = Journal of Virology | volume = 87 | issue = 1 | pages = 16–24 | date = January 2013 | pmid = 23077293 | pmc = 3536409 | doi = 10.1128/JVI.01853-12 }} IRF-3 controls the fate of the SeV-infected cells by triggering apoptosis and preventing persistence establishment; therefore its knock down allows persistence to occur. It was also reported that during SeV infection replication defective viral genomes (DVG) are forming{{cite journal | vauthors = Mercado-López X, Cotter CR, Kim WK, Sun Y, Muñoz L, Tapia K, López CB | title = Highly immunostimulatory RNA derived from a Sendai virus defective viral genome | journal = Vaccine | volume = 31 | issue = 48 | pages = 5713–5721 | date = November 2013 | pmid = 24099876 | pmc = 4406099 | doi = 10.1016/j.vaccine.2013.09.040 }} and selectively protect a subpopulation of host cells from death, therefore promoting the establishment of persistent infections.{{cite journal | vauthors = Xu J, Sun Y, Li Y, Ruthel G, Weiss SR, Raj A, Beiting D, López CB | title = Replication defective viral genomes exploit a cellular pro-survival mechanism to establish paramyxovirus persistence | journal = Nature Communications | volume = 8 | issue = 1 | pages = 799 | date = October 2017 | pmid = 28986577 | pmc = 5630589 | doi = 10.1038/s41467-017-00909-6 | bibcode = 2017NatCo...8..799X | author-link5 = Susan Weiss }}{{cite journal | vauthors = Genoyer E, López CB | title = Defective Viral Genomes Alter How Sendai Virus Interacts with Cellular Trafficking Machinery, Leading to Heterogeneity in the Production of Viral Particles among Infected Cells | journal = Journal of Virology | volume = 93 | issue = 4 | date = February 2019 | pmid = 30463965 | pmc = 6364009 | doi = 10.1128/JVI.01579-18 }} The possibility of establishing a chronic viral infection was further demonstrated in Sendai virus-infected ovine fibroblasts. In nature enzootic disease patterns suggest that the virus can be latent and can be cleared over the course of a year.{{cite journal | vauthors = Faísca P, Desmecht D | title = Sendai virus, the mouse parainfluenza type 1: a longstanding pathogen that remains up-to-date | journal = Research in Veterinary Science | volume = 82 | issue = 1 | pages = 115–125 | date = February 2007 | pmid = 16759680 | doi = 10.1016/j.rvsc.2006.03.009 }}

One recognized feature of the Sendai virus, shared with members of its genus, is the ability to induce syncytia formation in vivo and in vitro in eukaryotic cell cultures.{{cite journal |vauthors=Rawling J, Cano O, Garcin D, Kolakofsky D, Melero JA |title=Recombinant Sendai viruses expressing fusion proteins with two furin cleavage sites mimic the syncytial and receptor-independent infection properties of respiratory syncytial virus |journal=Journal of Virology |volume=85 |issue=6 |pages=2771–80 |date=March 2011 |pmid=21228237 |pmc=3067931 |doi=10.1128/JVI.02065-10}} The formation of syncytium helps the virus to avoid neutralizing antibodies of the host organism during the spread of infection. The mechanism for this process is fairly well understood and is very similar to the fusion process employed by the virion to facilitate cellular entry. The activities of the receptor binding hemagglutinin-neuraminidase protein is solely responsible for inducing close interaction between the virus envelope and the cellular membrane.

However, it is the F protein (one of many membrane fusion proteins) that, when triggered by local dehydration{{cite journal |vauthors=Hoekstra D, Klappe K, Hoff H, Nir S |title=Mechanism of fusion of Sendai virus: role of hydrophobic interactions and mobility constraints of viral membrane proteins. Effects of polyethylene glycol |journal=The Journal of Biological Chemistry |volume=264 |issue=12 |pages=6786–92 |date=April 1989 |doi=10.1016/S0021-9258(18)83498-6 |pmid=2540161|doi-access=free }} and a conformational change in the bound HN protein,{{cite journal |vauthors=Takimoto T, Taylor GL, Connaris HC, Crennell SJ, Portner A |title=Role of the hemagglutinin-neuraminidase protein in the mechanism of paramyxovirus-cell membrane fusion |journal=Journal of Virology |volume=76 |issue=24 |pages=13028–33 |date=December 2002 |pmid=12438628 |pmc=136693 |doi=10.1128/JVI.76.24.13028-13033.2002}} actively inserts into the cellular membrane, which causes the envelope and the membrane to merge, followed shortly by virion entry. When the HN and F protein are manufactured by the cell and expressed on the surface, the same process may occur between adjacent cells, causing extensive membrane fusion and resulting in the formation of a syncytium.{{cite journal |vauthors=Novick SL, Hoekstra D |title=Membrane penetration of Sendai virus glycoproteins during the early stages of fusion with liposomes as determined by hydrophobic photoaffinity labeling |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=85 |issue=20 |pages=7433–7 |date=October 1988 |pmid=2845406 |pmc=282205 |doi=10.1073/pnas.85.20.7433 |bibcode=1988PNAS...85.7433N|doi-access=free }}

Using the model of cellular hepatocarcinoma (Hep G2), it has been shown that Sendai virus recruits the cellular protein villin for cell fusion and syncytia formation. The villin-actin interaction regulates the fusion of the viral envelope and the cell membrane. Thus, villin is a host cell cofactor that regulates the fusion process.{{cite journal | vauthors = Chandra S, Kalaivani R, Kumar M, Srinivasan N, Sarkar DP | title = Sendai virus recruits cellular villin to remodel actin cytoskeleton during fusion with hepatocytes | journal = Molecular Biology of the Cell | volume = 28 | issue = 26 | pages = 3801–3814 | date = December 2017 | pmid = 29074568 | pmc = 5739296 | doi = 10.1091/mbc.e17-06-0400 | veditors = Bassereau P }} Its down-regulation with siRNA inhibits SeV infection of Hep G2 cells.

The cell fusion property of SeV was utilized by Köhler and Milstein, who published an article in 1975 outlining a revolutionary method of manufacturing monoclonal antibodies. In need of a reliable method to produce large quantities of a specific antibody, the two merged a monoclonal B cell, exposed to a chosen antigen, and a myeloma tumor cell to produce hybridomas, capable of being grown indefinitely and of producing significant amounts of an antibody specifically targeting the chosen antigen. Though more efficient methods of creating such hybrids have since been found, Köhler and Milstein first used Sendai virus to create their revolutionary cells.

File:Sensitivity of different cell lines to Sendai virus infection.tif

File:Cellular spread of Sendai virus.jpg were stained with DAPI blue fluorescent dye. Photographs were taken immediately after the addition of virus to the cells and 26 hours later.]]

Scientific studies show that the following cell lines are susceptible to SeV infection to varying degrees.

Some of these cells (for example, LLC MK2, 4647 and HEK 293) do not express a protease that processes fusion protein F0 of Sendai virus; therefore, they produce non-infectious virions.

Type 1 IFN inhibits the SeV production in normal human respiratory cells, but fails of doing it in human cells that originates from variable malignancies such as U937, Namalwa, and A549.

Variable cell cultures obtained from tumors have different sensitivity to SeV, and can also produce the virus in different quantities. There are multiple factors that are responsible for this variability. For example, an inverse correlation was observed between cells sensitivity to SeV infection and constitutive mRNA expression levels of TLR 3 and TLR 7 in primary cultures of prostate cancer. Thus, defective TLR-activated IFN signaling is one of these factors.

File:Sendaivirusdirectevolution1.jpg activity after adapting to growth in cell cultures]]

SeV strain variants adapted for growth in different cells have different properties. One study shows that the SeV variant adapted for growth in LLC-MK2 cells and the SeV variant adapted for growth in embryonated eggs differ by two amino acids in the HN protein. This difference results in different neuraminidase conformations around the receptor binding site and variations in neuraminidase activity between the two viral variants.{{cite journal |vauthors=Itoh M, Wang XL, Suzuki Y, Homma M |title=Mutation of the HANA protein of Sendai virus by passage in eggs |journal=Virology |volume=190 |issue=1 |pages=356–64 |date=September 1992 |pmid=1326808 |doi=10.1016/0042-6822(92)91222-g}} Another research study shows that SeV variants, adapted to grow in cell culture 4647 (African green monkey kidney cells) and in HEK 293 (human embryonic kidney cells) instead of embryonated chicken eggs, also acquire mutations in HN gene and both SeV variants lost their oncolytic activity.{{cite journal |vauthors=Zainutdinov SS, Kochneva GV, Netesov SV, Chumakov PM, Matveeva OV |title=Directed evolution as a tool for the selection of oncolytic RNA viruses with desired phenotypes |journal=Oncolytic Virotherapy |volume=8 |pages=9–26 |date=2019 |pmid=31372363 |pmc=6636189 |doi=10.2147/OV.S176523 |doi-access=free }}

File:Vaccines-08-00206-g001.jpg

Ovine blood-derived and alveolar macrophages can be infected with SeV ex vivo. Experiments with a virus construct with an inserted green fluorescent protein (SeV-GFP) showed that infection reaches 100% of cells in 48 hours. Primary cell cultures of ovine skin fibroblasts can also be infected and also achieve 100% GFP positivity. In fibroblasts, an intracellular virus-associated GFP expression was stable at least for more than a dozen passages in cell culture. However, an infectious virus was not produced in these ovine cells. This fact was demonstrated by the transfer of supernatants from SeV-infected cells into fresh cultures.{{cite journal | vauthors = Pablo-Maiso L, Echeverría I, Rius-Rocabert S, Luján L, Garcin D, Andrés D, Nistal-Villán E, Reina R | title = Sendai Virus, a Strong Inducer of Anti-Lentiviral State in Ovine Cells | journal = Vaccines | volume = 8 | issue = 2 | pages = 206 | date = April 2020 | pmid = 32365702 | pmc = 7349755 | doi = 10.3390/vaccines8020206 | doi-access = free }} In addition, human skin fibroblasts can be infected with Sendai virus. SeV can replicate to high titers in human monocyte-derived DCs.

Most often, SeV infection initiates an apoptotic program in the host cells, which leads to the death of target cells without interrupting the life cycle of the virus. However, paramyxoviruses, including SeV, can cause persistent infection in primary cell cultures that does not kill cells or turn off cellular RNA transcription and translation. It has been demonstrated that mouse connective tissues cells (L-929) and hamster kidney fibroblasts (BHK-21) can become infected with Sendai virus and the infection can be persistent. The possibility of establishing a persistent viral infection was demonstrated in SeV-infected ovine fibroblasts.

All Sendai virus strains belong to the same serotype. The origin of many strains of SeV was described in 1978. Some strains such as Ohita and Hamamatsu{{cite journal |vauthors=Sakaguchi T, Kiyotani K, Sakaki M, Fujii Y, Yoshida T |title=A field isolate of Sendai virus: its high virulence to mice and genetic divergence form prototype strains |journal=Archives of Virology |volume=135 |issue=1–2 |pages=159–64 |date=March 1994 |pmid=8198441 |doi=10.1007/bf01309773 |s2cid=12180965}} were described later. Ohita and Hamanatsu strains were isolated from separate epidemics in laboratory mice.{{cite journal |vauthors=Itoh M, Isegawa Y, Hotta H, Homma M |title=Isolation of an avirulent mutant of Sendai virus with two amino acid mutations from a highly virulent field strain through adaptation to LLC-MK2 cells |journal=The Journal of General Virology |volume=78 |issue=12 |pages=3207–15 |date=December 1997 |pmid=9400971 |doi=10.1099/0022-1317-78-12-3207 | doi-access = free}}{{cite journal |vauthors=Kiyotani K, Takao S, Sakaguchi T, Yoshida T |title=Immediate protection of mice from lethal wild-type Sendai virus (HVJ) infections by a temperature-sensitive mutant, HVJpi, possessing homologous interfering capacity |journal=Virology |volume=177 |issue=1 |pages=65–74 |date=July 1990 |pmid=2162116 |doi=10.1016/0042-6822(90)90460-9}} According to the personal memory of Alisa G. Bukrinskaya, who has co-authored numerous publications related to SeV along with Prof. Viktor M. Zhdanov, starting in 1961,{{cite journal |vauthors=Zhdanov VM, Bukrinskaya AG |title=Autoradiographic study of the penetration of Sendai virus into tissue culture cells. I. Preparation of Sendai virus labelled with radioactive isotopes |journal=Problems of Virology |volume=6 |pages=588–93 |date=1961 |pmid=14040447}} the Moscow strain of SeV was obtained by Prof. Viktor M. Zhdanov of the Ivanovsky Institute of Virology from Japan in the late 1950s or early 1960s, It is reported{{cite journal |vauthors=Shi LY, Li M, Yuan LJ, Wang Q, Li XM |title=A new paramyxovirus, Tianjin strain, isolated from common cotton-eared marmoset: genome characterization and structural protein sequence analysis |journal=Archives of Virology |volume=153 |issue=9 |pages=1715–23 |date=2008 |pmid=18696006 |doi=10.1007/s00705-008-0184-9 |s2cid=6151471 | doi-access = free}} that the BB1 strain{{cite journal |vauthors=Yang Y, Ren L, Dong X, Wu X |date=2005-05-01 |title=108. The Complete Nucleotide Sequence of Sendai Virus Isolate BB1 and Comparison with Other Isolates |journal=Molecular Therapy |volume=11 |pages=S44 |doi=10.1016/j.ymthe.2005.06.469|doi-access=free}} derived from the Moscow virus strain. The strain BB1 was given to the researchers of Institute of Viral Disease Control and Prevention, Beijing, China by researchers of Ivanovsky Institute of Virology, Moscow, Russia in the 1960s.

A field SeV isolate, that is attenuated through egg-passages, is less virulent for mouse respiratory cells.{{cite journal |vauthors=Kiyotani K, Sakaguchi T, Fujii Y, Yoshida T |title=Attenuation of a field Sendai virus isolate through egg-passages is associated with an impediment of viral genome replication in mouse respiratory cells |journal=Archives of Virology |volume=146 |issue=5 |pages=893–908 |date=2001 |pmid=11448028 |doi=10.1007/s007050170123 |s2cid=21947750 }} Therefore, the strains that were isolated from animals a few decades ago and went through multiple passages in eggs are less virulent for mice in comparison with the strains that are fresh field isolates.

{{See also|Defective interfering particle}}

Defective interfering (DI) genomes or defective viral genomes (DVGs) or defective interfering particles (DIPs) are replication defective viral RNA products generated during viral infections by many types of viruses, including SeV.{{cite journal | vauthors = Kolakofsky D | title = Isolation and characterization of Sendai virus DI-RNAs | journal = Cell | volume = 8 | issue = 4 | pages = 547–555 | date = August 1976 | pmid = 182384 | doi = 10.1016/0092-8674(76)90223-3 | s2cid = 32399729 }} It has been experimentally established that DI genomes can be readily produced by viral infection at high multiplicity.{{cite journal | vauthors = Kolakofsky D | title = Studies on the generation and amplification of sendai virus defective-interfering genomes | journal = Virology | volume = 93 | issue = 2 | pages = 589–593 | date = March 1979 | pmid = 222059 | doi = 10.1016/0042-6822(79)90263-0 }}{{cite journal | vauthors = Killip MJ, Young DF, Gatherer D, Ross CS, Short JA, Davison AJ, Goodbourn S, Randall RE | title = Deep sequencing analysis of defective genomes of parainfluenza virus 5 and their role in interferon induction | journal = Journal of Virology | volume = 87 | issue = 9 | pages = 4798–4807 | date = May 2013 | pmid = 23449801 | pmc = 3624313 | doi = 10.1128/JVI.03383-12 }} A single amino acid substitution in a nucleoprotein (NP) causes an increased production rate of DI genomes in the SeV Cantell strain, which is known for its particularly strong induction of interferon beta (IFN-β) during viral infection.{{cite journal | vauthors = Yoshida A, Kawabata R, Honda T, Sakai K, Ami Y, Sakaguchi T, Irie T | title = A Single Amino Acid Substitution within the Paramyxovirus Sendai Virus Nucleoprotein Is a Critical Determinant for Production of Interferon-Beta-Inducing Copyback-Type Defective Interfering Genomes | journal = Journal of Virology | volume = 92 | issue = 5 | date = March 2018 | pmid = 29237838 | pmc = 5809723 | doi = 10.1128/JVI.02094-17 }} It has been shown that DI are responsible for this strong IFN-β induction.{{cite journal |vauthors=Strahle L, Garcin D, Kolakofsky D |date=July 2006 |title=Sendai virus defective-interfering genomes and the activation of interferon-beta |journal=Virology |volume=351 |issue=1 |pages=101–111 |doi=10.1016/j.virol.2006.03.022 |pmid=16631220 |doi-access=free}} Other genomic change such as loss of the Sendai virus C-protein has also been demonstrated to cause accumulation of DI genomes.{{cite journal | vauthors = Sánchez-Aparicio MT, Garcin D, Rice CM, Kolakofsky D, García-Sastre A, Baum A | title = Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA | journal = The Journal of General Virology | volume = 98 | issue = 6 | pages = 1282–1293 | date = June 2017 | pmid = 28631605 | pmc = 5962894 | doi = 10.1099/jgv.0.000815 }}

*The sequence of Enders strain is available from the US patent [https://patents.google.com/patent/US9637758B2/en Modified Sendai virus vaccine and imaging vector]

Sendai virus can be produced using specific pathogen-free (SPF) embryonated chicken eggs.{{cite journal | vauthors = Tatsumoto N, Arditi M, Yamashita M | title = Sendai Virus Propagation Using Chicken Eggs | journal = Bio-Protocol | volume = 8 | issue = 18 | date = September 2018 | pmid = 30370318 | pmc = 6200407 | doi = 10.21769/BioProtoc.3009 }} Sendai virus, adapted to grow in cell culture instead of chicken eggs, loses its oncolytic activity.

The Sendai virus titer can be evaluated by serial end point 10x dilution assay of the virus-containing material in embryonated chicken eggs. This assay evaluates the final dilution that may cause a viral infection in 50% of inoculated eggs. This EID50 assay is used to quantify titer for many viruses that can be grown in eggs.{{cite journal | vauthors = Pappas C, Matsuoka Y, Swayne DE, Donis RO | title = Development and evaluation of an Influenza virus subtype H7N2 vaccine candidate for pandemic preparedness | journal = Clinical and Vaccine Immunology | volume = 14 | issue = 11 | pages = 1425–1432 | date = November 2007 | pmid = 17913860 | pmc = 2168170 | doi = 10.1128/CVI.00174-07 }}{{cite journal | vauthors = Racaniello V | date = 13 July 2009 | title = Measurement of viruses by end-point dilution assay | journal = Virology Blog | volume = 27 | pages = 493–497 | url = http://virology.ws/2009/07/13/measurement-of-viruses-by-end-point-dilution-assay/ }} The measurement of virus titer obtained from this assay is expressed as an embryonic infectious dose 50% (EID50). The SeV titer can also be assessed by using plaque assay in [https://www.atcc.org/products/all/CCL-7.aspx LLC-MK2] cells{{cite journal | vauthors = Tatsumoto N, Miyauchi T, Arditi M, Yamashita M | title = Quantification of Infectious Sendai Virus Using Plaque Assay | journal = Bio-Protocol | volume = 8 | issue = 21 | date = November 2018 | pmid = 30547053 | pmc = 6289198 | doi = 10.21769/BioProtoc.3068 }} and by serial end point 2x dilution hemagglutination assay (HA).{{cite book |vauthors=Killian ML |chapter=Hemagglutination Assay for the Avian Influenza Virus |title=Avian Influenza Virus |series=Methods in Molecular Biology |volume=436 |pages=47–52 |date=2008 |publisher=Humana Press |location=Totowa, NJ |pmid=18370040 |doi=10.1007/978-1-59745-279-3_7 |isbn=978-1-58829-939-0}} However, the HA test is less reliable than the EID50 or PFU tests because it does not always indicate the presence of a viable virus in a sample. The dead virus might demonstrate high HA titers.

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Murine respirovirus

Murine respirovirus

Murine respirovirus

Murine respirovirus