Ranavirus

The Ranaviruses, like the Megalocytiviruses, are an emerging group of closely related dsDNA viruses which cause systemic infections in a wide variety of wild and cultured fresh and saltwater fishes. As with Megalocytiviruses, Ranavirus outbreaks are therefore of considerable economic importance in aquaculture, as epizootics can result in moderate fish loss or mass mortality events of cultured fishes. Unlike Megalocytiviruses, however, Ranavirus infections in amphibians have been implicated as a contributing factor in the global decline of amphibian populations.{{Cite journal|last1=Teacher|first1=A. G. F.|last2=Cunningham|first2=A. A.|last3=Garner|first3=T. W. J.|date=2010-06-10|title=Assessing the long-term impact of Ranavirus infection in wild common frog populations: Impact of Ranavirus on wild frog populations|journal=Animal Conservation|volume=13|issue=5|pages=514–522|doi=10.1111/j.1469-1795.2010.00373.x|s2cid=85889833 }}{{Cite journal|last1=Price|first1=Stephen J.|last2=Garner|first2=Trenton W.J.|last3=Nichols|first3=Richard A.|author-link4=Francois Balloux|last4=Balloux|first4=François|last5=Ayres|first5=César|last6=Mora-Cabello de Alba|first6=Amparo|last7=Bosch|first7=Jaime|date=November 2014|title=Collapse of Amphibian Communities Due to an Introduced Ranavirus|journal=Current Biology|volume=24|issue=21|pages=2586–91|doi=10.1016/j.cub.2014.09.028|pmid=25438946|doi-access=free|bibcode=2014CBio...24.2586P |hdl=10261/123917|hdl-access=free}} The impact of Ranaviruses on amphibian populations has been compared to the chytrid fungus Batrachochytrium dendrobatidis, the causative agent of chytridiomycosis.{{cite journal | doi=10.1016/j.virol.2003.08.001 | title=Genomic sequence of a ranavirus (family Iridoviridae) associated with salamander mortalities in North America | year=2003 | journal=Virology | volume=316 | pages=90–103 | pmid=14599794 |first1=James K |last1=Jancovich |first2=Jinghe |last2=Mao |first3=V.Gregory |last3=Chinchar |first4=Christopher |last4=Wyatt |first5=Steven T |last5=Case |first6=Sudhir |last6=Kumar |first7=Graziela |last7=Valente |first8=Sankar |last8=Subramanian |first9=Elizabeth W |last9=Davidson | first10=James P |last10=Collins |first11=Bertram L |last11=Jacobs | issue=1 |doi-access=free }}{{cite journal|doi=10.1890/02-0374|title=Intraspecific Reservoirs: Complex Life History and the Persistence of a Lethal Ranavirus|journal=Ecology|volume=85|issue=2|pages=560|year=2004|last1=Brunner|first1=Jesse L.|last2=Schock|first2=Danna M.|last3=Davidson|first3=Elizabeth W.|last4=Collins|first4=James P.|bibcode=2004Ecol...85..560B }}{{cite journal|doi = 10.1111/j.1461-0248.2005.00735.x|title = Susceptibility of Italian agile frog populations to an emerging strain of Ranavirus parallels population genetic diversity|year = 2005|author = Pearman, Peter B.|journal = Ecology Letters|volume = 8|issue = 4|pages = 401|last2 = Garner|first2 = Trenton W. J.| bibcode=2005EcolL...8..401P }} In the UK, the severity of disease outbreaks is thought to have increased due to climate change.{{Cite journal|last1=Price|first1=Stephen J.|last2=Leung|first2=William T. M.|last3=Owen|first3=Christopher J.|last4=Puschendorf|first4=Robert|last5=Sergeant|first5=Chris|last6=Cunningham|first6=Andrew A.|last7=Balloux|first7=Francois|last8=Garner|first8=Trenton W. J.|last9=Nichols|first9=Richard A.|date=2019-05-09|title=Effects of historic and projected climate change on the range and impacts of an emerging wildlife disease|journal=Global Change Biology|volume=25|issue=8|pages=2648–60|doi=10.1111/gcb.14651|pmid=31074105 |bibcode=2019GCBio..25.2648P |issn=1354-1013|hdl=10026.1/13802|s2cid=149444899 |hdl-access=free}}

Rana is derived from the Latin for "frog",{{OEtymD|frog}} reflecting the first isolation of a Ranavirus in 1960s from the Northern leopard frog (Lithobates pipiens).{{cite journal | last1 = Granoff | first1 = A | last2 = Came | first2 = PE | last3 = Rafferty | first3 = KA | title = The isolation and properties of viruses from Rana pipiens: their possible relationship to the renal adenocarcinoma of the leopard frog | journal = Annals of the New York Academy of Sciences | volume = 126 | issue = 1 | pages = 237–255 | year = 1965 | pmid = 5220161 | doi = 10.1111/j.1749-6632.1965.tb14278.x| bibcode = 1965NYASA.126..237G | s2cid = 1534726 }}{{cite journal | last1 = Rafferty | first1 = KA | title = The cultivation of inclusion-associated viruses from Lucke tumor frogs | journal = Annals of the New York Academy of Sciences | volume = 126 | issue = 1 | pages = 3–21 | year = 1965 | pmid = 5220167 | doi = 10.1111/j.1749-6632.1965.tb14266.x| bibcode = 1965NYASA.126....3R | s2cid = 38763155 }}

File:Reptiles, Amphibians in US Succumbing to Deadly Ranavirus.ogv report about Ranavirus]]

The ranaviruses appear to have evolved from a fish virus which subsequently infected amphibians and reptiles.{{cite journal | last1 = Jancovich | first1 = JK | last2 = Bremont | first2 = M | last3 = Touchman | first3 = JW | last4 = Jacobs | first4 = BL | year = 2010 | title = Evidence for multiple recent host species shifts among the Ranaviruses (family Iridoviridae) | journal = J Virol | volume = 84 | issue = 6| pages = 2636–47 | doi = 10.1128/JVI.01991-09 | pmid = 20042506 | pmc = 2826071 }}

• Wood frogs (Lithobates sylvaticus)
• American Bullfrog (Lithobates catesbieanus)
• Pickerel Frog

• Green pythons (Chondropython viridis){{cite journal|vauthors=Hyatt AD, Williamson M, Coupar BE, Middleton D, Hengstberger SG, Gould AR, Selleck P, Wise TG, Kattenbelt J, Cunningham AA, Lee J |title=First identification of a ranavirus from green pythons (Chondropython viridis)|journal=Journal of Wildlife Diseases|volume=38|issue=2|pages=239–52|pmid=12038121|year=2002|doi=10.7589/0090-3558-38.2.239|s2cid=17427050 }}
• Burmese star tortoises (Geochelone platynota)
• Leopard tortoise (Geochelone pardalis){{cite journal|author1=Benetka V.|year=2007|title=First report of an iridovirus (genus Ranavirus) infection in a leopard tortoise (Geochelone pardalis pardalis)|journal= Vet Med Austria |volume=94|pages=243–8|url=http://www.schildkroeten-sfb.ch/fileadmin/docs/news/729-pantherschildkroete.pdf}}
• Gopher tortoises (Gopherus polyphemus)
• Mountain lizard (Lacerta monticola){{cite journal|title=New viruses from Lacerta monticola (Serra da Estrela, Portugal): Further evidence for a new group of nucleo-cytoplasmic large deoxyriboviruses (NCLDVs)|journal=Microscopy and Microanalysis |volume=17 |issue=1 |pages=101–8 |doi=10.1017/S143192761009433X |pmid=21138619|year=2011 |last1=De Matos |first1=A. P. |last2=Caeiro |first2=M. F. |last3=Papp |first3=T |last4=Matos |first4=B. A. |last5=Correia |first5=A. C. |last6=Marschang |first6=R. E. |bibcode=2011MiMic..17..101A |s2cid=21932480 }}
• Eastern box turtles (Terrapene carolina carolina){{cite journal | last1 = Mao | first1 = J | last2 = Hedrick | first2 = RP | last3 = Chinchar | first3 = VG | year = 1997 | title = Molecular characterization, sequence analysis, and taxonomic position of newly isolated fish iridoviruses | journal = Virology | volume = 229 | issue = 1| pages = 212–220 | doi = 10.1006/viro.1996.8435 | pmid = 9123863 | doi-access = free }}
• Florida box turtles (Terrapene carolina bauri)
• Western ornate box turtles (Terrapene ornata){{cite journal|title= Experimental transmission and induction of ranaviral disease in Western Ornate box turtles (Terrapene ornata ornata) and red-eared sliders (Trachemys scripta elegans)|journal=Veterinary Pathology|volume=44|issue=3|pages=285–97|pmid=17491069|year=2007|last1=Johnson|first1=A. J.|last2=Pessier|first2=A. P.|last3=Jacobson|first3=E. R.|doi=10.1354/vp.44-3-285|doi-access=free}}
• Spur-thighed tortoises (Testudo graeca)Blahak S., Uhlenbrok C. "Ranavirus infections in European terrestrial tortoises in Germany". Proceedings of the 1st International Conference on Reptile and Amphibian Medicine; Munich, Germany. 4–7 March 2010; pp. 17–23
• Hermann's tortoises (Testudo hermanni)
• Egyptian tortoises (Testudo kleinmanni)
• Russian tortoises (Testudo horsfieldii)
• Marginated tortoises (Testudo marginata)
• Red-eared sliders (Trachemys scripta elegans)
• Common snapping turtles (Chelydra serpentina){{cite journal |title=First report of ranavirus mortality in a common snapping turtle Chelydra serpentina |journal=Diseases of Aquatic Organisms |issue=3 |pages=221–7 |doi=10.3354/dao03324 |year=2019 |last1=McKenzie |first1=C. M. |last2=Piczak |first2=M.L. |last3=Snyman |first3=H. N. |last4=Joseph |first4=T. |last5=Theijin |first5=C. |last6=Chow-Fraser |first6=P. |last7=Jardine |first7=C. M. |volume=132 |pmid=31188138 |s2cid=92405818 |url=https://www.int-res.com/articles/dao2018/132/d132p221.pdf }}
• Chinese softshell turtles (Pelodiscus sinensis){{cite journal|title= A new iridovirus isolated from soft-shelled turtle|journal=Virus Research|volume=63|issue=1–2|pages=147–51|pmid=10509727|doi=10.1016/S0168-1702(99)00069-6|year=1999|last1=Chen|first1=Z. X.|last2=Zheng|first2=J. C.|last3=Jiang|first3=Y. L.}}
• Common flat-tail gecko (Uroplatus fimbriatus){{cite journal|title=Isolation of a ranavirus from a gecko (Uroplatus fimbriatus)|journal=Journal of Zoo and Wildlife Medicine |volume=36|issue=2|pages=295–300|jstor=20096453|pmid=17323572|year=2005|last1=Marschang|first1=R. E.|last2=Braun|first2=S|last3=Becher|first3=P|doi=10.1638/04-008.1|s2cid=20616080 }}

• Eastern Fence Lizard (Sceloporus undulatus) {{cite journal|title=Detection of Ranavirus in Eastern Fence Lizards and Eastern Box Turtles in Central Virginia|journal=Northeastern Naturalist|volume=25|issue=3|pages=391–8|year=2018|last1=Goodman|first1=R.|last2=Hargadon|first2=K|last3=Carter|first3=E. |doi=10.1656/045.025.0306|s2cid=91510246 }}

The genus contains the following species, listed by scientific name and followed by the exemplar virus of the species:{{cite web|title=Virus Taxonomy: 2024 Release|url=https://ictv.global/taxonomy|publisher=International Committee on Taxonomy of Viruses|access-date=23 March 2025}}

• Ranavirus alytes1, Common midwife toad virus-E
• Ranavirus ambystoma1, Ambystoma tigrinum virus
• Ranavirus epinephelus1, Singapore grouper iridovirus
• Ranavirus gadus1, Cod iridovirus
• Ranavirus micropterus1, Largemouth bass virus
• Ranavirus perca1, Epizootic haematopoietic necrosis virus
• Ranavirus rana1, Frog virus 3

The family Iridoviridae is divided into seven genera which include Chloriridovirus, Iridovirus, Lymphocystivirus, Megalocytivirus, and Ranavirus. The genus Ranavirus contains three viruses known to infect amphibians (Ambystoma tigrinum virus (ATV), Bohle iridovirus (BIV), and frog virus 3).

Ranaviruses are large icosahedral DNA viruses measuring approximately 150 nm in diameter with a large single linear dsDNA genome of roughly 105 kbp{{cite book |vauthors=Williams T, Barbosa-Solomieu V, Chinchar GD |chapter=A decade of advances in iridovirus research |chapter-url=https://www.sciencedirect.com/science/article/abs/pii/S0065352705650063 |doi=10.1016/S0065-3527(05)65006-3 |veditors=Maramorosch K, Shatkin A |title=Advances in virus research |volume=65 |publisher=Academic Press |oclc=795776628 |date=2005 |isbn=978-0-12-039867-6 |pages=173–148 }} which codes for around 100 gene products.{{cite journal | last1 = Chinchar | first1 = VG | title = Ranaviruses (family Iridoviridae) emerging cold-blooded killers | journal = Archives of Virology | volume = 147 | issue = 3 | pages = 447–470 | year = 2002 | pmid = 11958449 | doi = 10.1007/s007050200000 | s2cid = 24928231 | doi-access = free }} The main structural component of the protein capsid is the major capsid protein (MCP).

Ranaviral replication is well studied using Frog virus 3 (FV3). Replication of FV3 occurs between 12 and 32 degrees Celsius. Ranaviruses enter the host cell by receptor-mediated endocytosis.{{cite journal|title=The genomic diversity and phylogenetic relationship in the family Iridoviridae|journal=Viruses|volume=2|issue=7|pages=1458–75|doi=10.3390/v2071458|pmid=21994690|year=2010|last1=Eaton|first1=Heather E.|last2=Ring|first2=Brooke A.|last3=Brunetti|first3=Craig R.|pmc=3185713|doi-access=free }} Viral particles are uncoated and subsequently move into the cell nucleus, where viral DNA replication begins via a virally encoded DNA polymerase.{{cite journal | last1 = Goorha | first1 = R | title = Frog virus 3 DNA replication occurs in two stages | journal = Journal of Virology | volume = 43 | issue = 2 | pages = 519–28 | year = 1982 | doi = 10.1128/JVI.43.2.519-528.1982 | pmid = 7109033| pmc = 256155}} Viral DNA then abandons the cell nucleus and begins the second stage of DNA replication in the cytoplasm, ultimately forming DNA concatemers. The viral DNA is then packaged via a headful mechanism into infectious virions.{{cite book |vauthors=Chinchar VG, Essbauer S, He JG, Hyatt A, Miyazaki T, Seligy V, Williams T |chapter=Family Iridoviridae |chapter-url= |veditors=Fauquet CM, Mayo MA, Maniloff J, Desselburger U, Ball LA |title=Virus Taxonomy, Eighth report of the International Committee on Taxonomy of Viruses |publisher=Academic Press |oclc=937237481 |date=2005 |isbn=978-0-12-249951-7 |pages=145–162 }} The ranavirus genome, like other iridoviral genomes is circularly permuted and exhibits terminally redundant DNA.

There is evidence that ranavirus infections target macrophages as a mechanism for gaining entry to cells.

{{cite journal |last1=Girdhar |first1=Khyati |last2=Powis |first2=Amaya |last3=Raisingani |first3=Amol |last4=Chrudinová |first4=Martina |last5=Huang |first5=Ruixu |last6=Tran |first6=Tu |last7=Sevgi |first7=Kaan |last8=Dogus Dogru |first8=Yusuf |last9=Altindis |first9=Emrah |title=Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism |journal=Annual Review of Virology |date=29 September 2021 |volume=8 |issue=1 |pages=373–391|doi-access=free |doi=10.1146/annurev-virology-091919-102416 |pmid=34586876 |pmc=9175272 }}

Andrias davidianus ranavirus, isolated from the Chinese giant salamander, encodes a protein (Rad2 homolog) that has a key role in the repair of DNA by homologous recombination and in DNA double-strand break repair.{{cite journal |vauthors=Ke F, Zhang QY |title=ADRV 12L: A Ranaviral Putative Rad2 Family Protein Involved in DNA Recombination and Repair |journal=Viruses |volume=14 |issue=5 |pages= |date=April 2022 |pmid=35632650 |pmc=9146916 |doi=10.3390/v14050908 |doi-access=free}}

Transmission of ranaviruses is thought to occur by multiple routes, including contaminated soil, direct contact, waterborne exposure, and ingestion of infected tissues during predation, necrophagy or cannibalism.{{cite journal |last1=Brenes |first1=Roberto |last2=Gray |first2=Matthew J. |last3=Waltzek |first3=Thomas B. |last4=Wilkes |first4=Rebecca P. |last5=Miller |first5=Debra L. |title=Transmission of Ranavirus between Ectothermic Vertebrate Hosts |journal=PLOS ONE |date=25 March 2014 |volume=9 |issue=3 |pages=e92476 |doi=10.1371/journal.pone.0092476|pmid=24667325 |pmc=3965414 |bibcode=2014PLoSO...992476B |doi-access=free }}

Ranaviruses are relatively stable in aquatic environments, persisting several weeks or longer outside a host organism.{{cite journal | last1 = Gray | first1 = MJ | last2 = Miller | first2 = DL | last3 = Hoverman | first3 = JT | title = Ecology and pathology of amphibian ranaviruses | journal = Diseases of Aquatic Organisms | volume = 87 | issue = 3 | pages = 243–266 | year = 2009 | pmid = 20099417 | doi = 10.3354/dao02138| doi-access = free }}

Amphibian mass mortality events due to Ranavirus have been reported in Asia, Europe, North America, and South America. Ranaviruses have been isolated from wild populations of amphibians in Australia, but have not been associated with mass mortality on that continent.{{cite journal | last1 = Speare | first1 = R | last2 = Smith | first2 = JR | title = An iridovirus-like agent isolated from the ornate burrowing frog Limnodynastes ornatus in northern Australia | journal = Diseases of Aquatic Organisms | volume = 14 | pages = 51–57 | year = 1992 | doi = 10.3354/dao014051| doi-access = free }}{{cite journal | last1 = Cullen | first1 = BR | last2 = Owens | first2 = L | title = Experimental challenge and clinical cases of Bohle iridovirus (BIV) in native Australian anurans | journal = Diseases of Aquatic Organisms | volume = 49 | issue = 2 | pages = 83–92 | year = 2002 | pmid = 12078986 | doi=10.3354/dao049083| doi-access = free }}

Synthesis of viral proteins begins within hours of viral entry with necrosis or apoptosis occurring as early as a few hours post infection.{{cite journal | last1 = Chinchar | first1 = VG | last2 = Bryan | first2 = L | last3 = Wang | first3 = J | last4 = Long | first4 = S | last5 = Chinchar | first5 = GD |title = Induction of apoptosis in frog virus 3-infected cells | journal = Virology | volume = 306 | pages = 303–312 | year = 2003 | pmid = 12642103 | doi = 10.1016/S0042-6822(02)00039-9 | issue = 2| doi-access = free }}

==Seasonal disease dynamics==

There are several hypotheses for seasonal outbreak patterns observed for Ranavirosis mortality events.{{cite book |last1=Brunner |first1=Jesse L. |last2=Storfer |first2=Andrew |last3=Gray |first3=Matthew J. |last4=Hoverman |first4=Jason T. |chapter=Ranavirus Ecology and Evolution: From Epidemiology to Extinction |chapter-url=https://link.springer.com/chapter/10.1007/978-3-319-13755-1_4 |editor1-first=Matthew J. |editor1-last=Gray |editor2-first=V. Gregory |editor2-last=Chinchar |title=Ranaviruses: Lethal Pathogens of Ectothermic Vertebrates |date=2015 |publisher=Springer |isbn=978-3-319-13755-1 |page=71–104 |doi=10.1007/978-3-319-13755-1_4}} Ranaviruses grow in vitro between 8-30 °C, however for most isolates, warmer temperature result in faster viral replication. A combination of this optimal growth temperature along with shifts in larval amphibian susceptibility result in seasonal outbreak events most often observed during warm summer months.{{cite journal |last1=Green |first1=D E |last2=Converse |first2=K A |last3=Schrader |first3=A K |title=Epizootiology of sixty-four amphibian morbidity and mortality events in the USA, 1996–2001 |journal=Domestic Animal/Wildlife Interface: Issues for Disease Control, Conservation, Sustainable Food Production, and Emerging Diseases |year=2002 |volume=969 |issue=1 |pages=323–339 |doi=10.1111/j.1749-6632.2002.tb04400.x |pmid=12381613 |bibcode=2002NYASA.969..323G |s2cid=33944909}} Amphibian mortality events are often observed as larval amphibians reach late Gosner stages approaching metamorphosis.{{cite journal |last1=Green |first1=D E |last2=Converse |first2=K A |title=Diseases of frogs and toads |journal=Wildlife Diseases: Landscape Epidemiology, Spatial Distribution, and Utilization of Remote Sensing Technology. |date=2005 |pages=89–117 |url=http://pubs.er.usgs.gov/publication/85615}} As larval amphibians reach metamorphic stages of development, their immune system is reorganized prior to the development of adult tissues.{{cite journal |last1=Rollins-Smith |first1=L A |title=Metamorphosis and the amphibian immune system |journal=Immunological Reviews |date=1998 |volume=166 |pages=221–230 |doi=10.1111/j.1600-065X.1998.tb01265.x|pmid=9914915 |s2cid=27561247 }} During this time period, amphibians are stressed, and their immune systems are down regulated. This decrease in immune function and warmer environmental temperatures allows for greater viral replication and cellular damage to occur. Across 64 mortality events in the United States 54% were found to occur between June-August.

The environmental persistence of Ranaviruses is not understood well, however in realistic environmental conditions the T90 value of an FV3-like virus is 1 day.{{cite journal |last1=Johnson |first1=A F |last2=Brunner |first2=J L |title=Persistence of an amphibian ranavirus in aquatic communities |journal=Diseases of Aquatic Organisms |date=2014 |volume=111 |issue=2 |pages=129–138 |doi=10.3354/dao02774|pmid=25266900 |doi-access=free }} The duration of persistence is likely affected by temperature and microbial conditions. It is unlikely that ranaviruses persist in the environment outside of host species between outbreak events.

Researchers have explored several pathogen reservoirs for the virus which might explain how the virus can persist within an amphibian community. In some amphibian populations, sub-clinically infected individuals may serve as reservoirs for the pathogen. These sub-clinically infected individuals are responsible for reintroduction of the virus to the larval population. With ranaviruses being capable of infected multiple taxa, and with there being differences in susceptibility between taxa, it is likely that sympatric fish and reptile species may serve as reservoirs for virus as well. Interclass transmission has been proven through the use of mesocosm studies.{{cite journal |last1=Brenes |first1=Roberto |last2=Gray |first2=MJ |last3=Waltzek |first3=TB |last4=Wilkes |first4=RP |last5=Miller |first5=DL |title=Transmission of Ranavirus between Ectothermic Vertebrate Hosts |journal=PLOS ONE |date=2014 |volume=9 |issue=3 |pages=e92476 |doi=10.1371/journal.pone.0092476|pmid=24667325 |pmc=3965414 |bibcode=2014PLoSO...992476B |doi-access=free }}

Gross lesions associated with Ranavirus infection include erythema, generalized swelling, hemorrhage, limb swelling, and swollen and friable livers.

• Decline in amphibian populations

{{Reflist|35em}}

{{Commons category|Ranavirus}}

{{Wikispecies-inline|List of viruses}}

• [https://ictv.global/report/chapter/iridoviridae/iridoviridae ICTV Online (10th) Report: Iridoviridae]
• [http://viralzone.expasy.org/all_by_species/585.html Viralzone: Ranavirus]
• [http://www.ranavirus.org Global Ranavirus Consortium]
• [https://library.oapen.org/handle/20.500.12657/27843 Ranaviruses: Lethal Pathogens of Ectothermic Vertebrates]

{{Baltimore classification}}

{{Taxonbar|from=Q3418768}}

Category:Iridoviridae

Category:Fish viral diseases

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Category:Virus genera