Influenza A virus#Structure and genetics

There are two methods of classification, one based on surface proteins (originally serotypes),{{cite journal | vauthors = Masurel N | title = Serological characteristics of a "new" serotype of influenza A virus: the Hong Kong strain | journal = Bulletin of the World Health Organization | volume = 41 | issue = 3 | pages = 461–468 | date = 1969 | pmid = 5309456 | pmc = 2427714 }} and the other based on its behavior, mainly the host animal.

File:InfluenzaNomenclatureDiagram.svgThere are two antigenic proteins on the surface of the viral envelope, hemagglutinin and neuraminidase.{{cite journal | vauthors = Johnson J, Higgins A, Navarro A, Huang Y, Esper FL, Barton N, Esch D, Shaw C, Olivo PD, Miao LY | title = Subtyping influenza A virus with monoclonal antibodies and an indirect immunofluorescence assay | journal = Journal of Clinical Microbiology | volume = 50 | issue = 2 | pages = 396–400 | date = February 2012 | pmid = 22075584 | pmc = 3264186 | doi = 10.1128/JCM.01237-11 }} Different influenza virus genomes encode different hemagglutinin and neuraminidase proteins. Based on their serotype, there are 18 known types of hemagglutinin and 11 types of neuraminidase.{{cite web |date=2 April 2013 |title=Influenza Type A Viruses and Subtypes |url=https://www.cdc.gov/flu/avianflu/influenza-a-virus-subtypes.htm |access-date=13 June 2013 |publisher=U.S. Centers for Disease Control and Prevention (CDC) |archive-date=1 June 2021 |archive-url=https://web.archive.org/web/20210601122204/https://www.cdc.gov/flu/avianflu/influenza-a-virus-subtypes.htm |url-status=live }}{{cite journal | vauthors = Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Donis RO | title = New world bats harbor diverse influenza A viruses | journal = PLOS Pathogens | volume = 9 | issue = 10 | pages = e1003657 | date = October 2013 | pmid = 24130481 | pmc = 3794996 | doi = 10.1371/journal.ppat.1003657 | title-link = doi | doi-access = free }} Subtypes of IAV are classified by their combination of H and N proteins. For example, "H5N1" designates an influenza A subtype that has a type-5 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein. Additionally, further variation exists within viral subtypes which may lead to significant differences in behavior.{{Cite web |date=27 February 2024 |title=Influenza Virus Genome Sequencing and Genetic Characterization |url=https://www.cdc.gov/flu/about/professionals/genetic-characterization.htm |archive-url=https://web.archive.org/web/20240327035015/https://www.cdc.gov/flu/about/professionals/genetic-characterization.htm |archive-date=27 March 2024 |access-date=19 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }}

By definition, the subtyping scheme only takes into account the two outer proteins, not the at least eight proteins internal to the virus.{{cite journal | vauthors = Eisfeld AJ, Neumann G, Kawaoka Y | title = At the centre: influenza A virus ribonucleoproteins | journal = Nature Reviews. Microbiology | volume = 13 | issue = 1 | pages = 28–41 | date = January 2015 | pmid = 25417656 | pmc = 5619696 | doi = 10.1038/nrmicro3367 }} Almost all possible combinations of H (1 through 16) and N (1 through 11) have been isolated from wild birds.{{Cite web |title=FluGlobalNet – Avian Influenza |url=https://science.vla.gov.uk/fluglobalnet/about_ai.html |access-date=5 June 2024 |website=science.vla.gov.uk}} H17 and H18 have only been discovered in bats.{{Cite web |date=17 June 2024 |title=Influenza A Subtypes and the Species Affected |url=https://www.cdc.gov/flu/other/animal-flu.html |access-date=18 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }}

Due to the high variability of the virus, subtyping is not sufficient to uniquely identify a strain of influenza A virus. To unambiguously describe a specific isolate of virus, researchers use the Influenza virus nomenclature,{{cite journal | vauthors = | title = A revision of the system of nomenclature for influenza viruses: a WHO memorandum | journal = Bulletin of the World Health Organization | volume = 58 | issue = 4 | pages = 585–591 | date = 1980 | pmid = 6969132 | pmc = 2395936 | quote = This Memorandum was drafted by the signatories listed on page 590 on the occasion of a meeting held in Geneva in February 1980. }} which describes, among other things, the subtype, year, and place of collection. Some examples include:{{cite web | title=Technical note: Influenza virus nomenclature | website=Pan American Health Organization | date=11 January 2023 | url=https://www.paho.org/en/documents/technical-note-influenza-virus-nomenclature | access-date=27 May 2024 | archive-date=10 August 2023 | archive-url=https://web.archive.org/web/20230810004651/http://www.paho.org/en/documents/technical-note-influenza-virus-nomenclature | url-status=live }}

• {{tt|A/Rio de Janeiro/62434/2021 (H3N2)}}.
• The starting {{tt|A}} indicates that the virus is an influenza A virus.
• {{tt|Rio de Janeiro}} indicates the place of collection. {{tt|62434}} is a laboratory sequence number. {{tt|2021}} (or just {{tt|21}}) indicates that the sample was collected in 2021. No species is mentioned so by default, the sample was collected from a human.
• {{tt|(H3N2)}} indicates the subtype of the virus.
• {{tt|A/swine/South Dakota/152B/2009 (H1N2)}}.
• This example shows an additional field before the place: {{tt|swine}}. It indicates that the sample was collected from a pig.
• {{tt|A/California/04/2009 A(H1N1)pdm09}}.
• This example carries an unusual designation in the last part: instead of a usual {{tt|(H1N1)}}, it uses {{tt|A(H1N1)pdm09}}. This was in order to distinguish the Pandemic H1N1/09 virus lineage from older H1N1 viruses.

{{See also|H5N1 genetic structure}}File:Viruses-10-00497-g001.png

The influenza A virus has a negative-sense, single-stranded, segmented RNA genome, enclosed in a lipid envelope. The virus particle (also called the "virion") is 80–120 nanometers in diameter, such that the smallest virions adopt an elliptical shape; larger virions have a filamentous shape.{{cite journal | vauthors = Dadonaite B, Vijayakrishnan S, Fodor E, Bhella D, Hutchinson EC | title = Filamentous influenza viruses | journal = The Journal of General Virology | volume = 97 | issue = 8 | pages = 1755–1764 | date = August 2016 | pmid = 27365089 | pmc = 5935222 | doi = 10.1099/jgv.0.000535 }}

Core – The central core of the virion contains the viral RNA genome, which is made of eight separate segments.{{cite journal | vauthors = Bouvier NM, Palese P | title = The biology of influenza viruses | journal = Vaccine | volume = 26 | issue = Suppl 4 | pages = D49–D53 | date = September 2008 | pmid = 19230160 | pmc = 3074182 | doi = 10.1016/j.vaccine.2008.07.039 }} The nucleoprotein (NP) coats the viral RNA to form a ribonucleoprotein that assumes a helical (spiral) configuration. Three large proteins (PB₁, PB₂, and PA), which are responsible for RNA transcription and replication, are bound to each segment of viral RNP.{{Cite web | vauthors = Shaffer C |date=7 March 2018 |title=Influenza A Structure |url=https://www.news-medical.net/life-sciences/Influenza-A-Structure.aspx |access-date=18 June 2024 |website=News-Medical }}{{Cite web |date=13 May 2010 |title=Virology of human influenza |url=https://www.who.int/europe/news-room/fact-sheets/item/virology-of-human-influenza |access-date=19 June 2024 |website=World Health Organization }}

Capsid – The matrix protein M1 forms a layer between the nucleoprotein and the envelope, called the capsid.

Envelope – The viral envelope consists of a lipid bilayer derived from the host cell. Two viral proteins; hemagglutinin (HA) and neuraminidase (NA), are inserted into the envelope and are exposed as spikes on the surface of the virion. Both proteins are antigenic; a host's immune system can react to them and produce antibodies in response. The M2 protein forms an ion channel in the envelope and is responsible for uncoating the virion once it has bound to a host cell.

The table below presents a concise summary of the influenza genome and the principal functions of the proteins which are encoded. Segments are conventionally numbered from 1 to 8 in descending order of length.{{cite journal | vauthors = Krammer F, Smith GJ, Fouchier RA, Peiris M, Kedzierska K, Doherty PC, Palese P, Shaw ML, Treanor J, Webster RG, García-Sastre A | title = Influenza | journal = Nature Reviews. Disease Primers | volume = 4 | issue = 1 | pages = 3 | date = June 2018 | pmid = 29955068 | pmc = 7097467 | doi = 10.1038/s41572-018-0002-y }}{{cite journal | vauthors = Jakob C, Paul-Stansilaus R, Schwemmle M, Marquet R, Bolte H | title = The influenza A virus genome packaging network – complex, flexible and yet unsolved | journal = Nucleic Acids Research | volume = 50 | issue = 16 | pages = 9023–9038 | date = September 2022 | pmid = 35993811 | doi = 10.1093/nar/gkac688 | pmc = 9458418 }}{{cite journal | vauthors = Dou D, Revol R, Östbye H, Wang H, Daniels R | title = Influenza A Virus Cell Entry, Replication, Virion Assembly and Movement | journal = Frontiers in Immunology | volume = 9 | pages = 1581 | date = 20 July 2018 | pmid = 30079062 | pmc = 6062596 | doi = 10.3389/fimmu.2018.01581 | doi-access = free }}{{cite journal | vauthors = Rashid F, Xie Z, Li M, Xie Z, Luo S, Xie L | title = Roles and functions of IAV proteins in host immune evasion | journal = Frontiers in Immunology | volume = 14 | pages = 1323560 | date = 13 December 2023 | pmid = 38152399 | pmc = 10751371 | doi = 10.3389/fimmu.2023.1323560 | doi-access = free }}

Three viral proteins - PB1, PB2, and PA – associate to form the RNA-dependent RNA polymerase (RdRp) which functions to transcribe and replicate the viral RNA.

Viral messenger RNA transcription – The RdRp complex transcribes viral mRNAs by using a mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. Host cell mRNA is cleaved near the cap to yield a primer for the transcription of positive-sense viral mRNA using the negative-sense viral RNA as a template.{{cite journal | vauthors = Decroly E, Canard B | title = Biochemical principles and inhibitors to interfere with viral capping pathways | journal = Current Opinion in Virology | volume = 24 | pages = 87–96 | date = June 2017 | pmid = 28527860 | pmc = 7185569 | doi = 10.1016/j.coviro.2017.04.003 }} The host cell then transports the viral mRNA into the cytoplasm where ribosomes manufacture the viral proteins.

Replication of the viral RNA – The replication of the influenza virus, unlike most other RNA viruses,{{Cite journal |last1=Rampersad |first1=Sephra |last2=Tennant |first2=Paula |date=2018 |title=Replication and Expression Strategies of Viruses |journal=Viruses |pages=55–82 |doi=10.1016/B978-0-12-811257-1.00003-6 |pmc=7158166|isbn=978-0-12-811257-1 }} takes place in the nucleus and involves two steps. The RdRp first of all transcribes the negative-sense viral genome into a positive-sense complimentary RNA (cRNA), then the cRNAs are used as templates to transcribe new negative-sense vRNA copies. These are exported from the nucleus and assemble near the cell membrane to form the core of new virions.

File:Genetic Relationships Among Human and Swine Influenza Viruses, 1918-2009 (7704014350).jpg

{{Also|Timeline of influenza}}

The predominant natural reservoir of influenza viruses is thought to be wild waterfowl.{{Cite book |title=The Threat of Pandemic Influenza: Are We Ready? Workshop Summary. Institute of Medicine (US) Forum on Microbial Threats |publisher=National Academies Press (US) |year=2005 |veditors=Mahmoud SM, Alison M, Knobler SL |location=Washington (DC) |chapter=1, The Story of Influenza. | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK22148/ }} The subtypes of influenza A virus are estimated to have diverged 2,000 years ago. Influenza viruses A and B are estimated to have diverged from a single ancestor around 4,000 years ago, while the ancestor of influenza viruses A and B and the ancestor of influenza virus C are estimated to have diverged from a common ancestor around 8,000 years ago.{{cite journal | vauthors = Suzuki Y, Nei M | title = Origin and evolution of influenza virus hemagglutinin genes | journal = Molecular Biology and Evolution | volume = 19 | issue = 4 | pages = 501–509 | date = April 2002 | pmid = 11919291 | doi = 10.1093/oxfordjournals.molbev.a004105 | publisher = Ocford Academic | title-link = doi | doi-access = free }}

Outbreaks of influenza-like disease can be found throughout recorded history. The first probable record is by Hippocrates in 412 BCE.{{Cite web |title=The History of Influenza |url=https://www.flu.com/Articles/2022/The-History-of-Influenza |access-date=20 June 2024 |website=www.flu.com }} The historian Fujikawa listed 46 epidemics of flu-like illness in Japan between 862 and 1868.{{cite journal | vauthors = Shimizu K | title = [History of influenza epidemics and discovery of influenza virus] | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 55 | issue = 10 | pages = 2505–2511 | date = October 1997 | pmid = 9360364 }} In Europe and the Americas, a number of epidemics were recorded through the Middle Ages and up to the end of the 19th century.File:Viruses-10-00497-g004.pngIn 1918-1919 came the first flu pandemic of the 20th century, known generally as the "Spanish flu", which caused an estimated 20 to 50 million deaths worldwide. It is now known that this was caused by an immunologically novel H1N1 subtype of influenza A.{{Cite web |date=20 March 2019 |title=CDC Archives : 1918 Pandemic (H1N1 virus) |url=https://archive.cdc.gov/#/details?url=https://www.cdc.gov/flu/pandemic-resources/1918-pandemic-h1n1.html |access-date=20 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC)}} The next pandemic took place in 1957, the "Asian flu", which was caused by a H2N2 subtype of the virus in which the genome segments coding for HA and NA appeared to have derived from avian influenza strains by reassortment, while the remainder of the genome was descended from the 1918 virus.{{cite book | collaboration = Institute of Medicine (US) Forum on Microbial Threats |chapter = The Story of Influenza |date=2005 | title = The Threat of Pandemic Influenza: Are We Ready? Workshop Summary |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK22148/ |access-date=20 June 2024 |publisher=National Academies Press (US) | vauthors = Knobler SL, Mack A, Mahmoud A, Lemon SM }} The 1968 pandemic ("Hong Kong flu") was caused by a H3N2 subtype in which the NA segment was derived from the 1957 virus, while the HA segment had been reassorted from an avian strain of influenza.

In the 21st century, a strain of H1N1 flu (since titled "H1N1pdm09") was antigenically very different from previous H1N1 strains, leading to a pandemic in 2009. Because of its close resemblance to some strains circulating in pigs, this became known as "swine flu".{{Cite web |date=11 June 2019 |title=2009 H1N1 Pandemic (H1N1pdm09 virus) |url=https://archive.cdc.gov/#/details?url=https://www.cdc.gov/flu/pandemic-resources/2009-h1n1-pandemic.html |access-date=21 June 2024 |website=CU.S. Centers for Disease Control and Prevention (CDC)}}

Influenza A virus continues to circulate and evolve in birds and pigs. Almost all possible combinations of H (1 through 16) and N (1 through 11) have been isolated from wild birds. As of June 2024, two particularly virulent IAV strains - H5N1 and H7N9 – are predominant in wild bird populations. These frequently cause outbreaks in domestic poultry, with occasional spillover infections in humans who are in close contact with poultry.{{Cite web |date=26 March 2021 |title=The next pandemic: H5N1 and H7N9 influenza? |url=https://www.gavi.org/vaccineswork/next-pandemic/h5n1-and-h7n9-influenza |access-date=21 June 2024 |website=Gavi, the Vaccine Alliance }}{{Cite web |date=3 October 2023 |title=Influenza (Avian and other zoonotic) |url=https://www.who.int/news-room/fact-sheets/detail/influenza-(avian-and-other-zoonotic) |access-date=21 June 2024 |website=World Health Organization }}

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses.{{cite journal | vauthors = Sanjuán R, Nebot MR, Chirico N, Mansky LM, Belshaw R | title = Viral mutation rates | journal = Journal of Virology | volume = 84 | issue = 19 | pages = 9733–9748 | date = October 2010 | pmid = 20660197 | pmc = 2937809 | doi = 10.1128/JVI.00694-10 }} The segmentation of the influenza A virus genome facilitates genetic recombination by segment reassortment in hosts who become infected with two different strains of influenza viruses at the same time.{{cite journal | vauthors = Kou Z, Lei FM, Yu J, Fan ZJ, Yin ZH, Jia CX, Xiong KJ, Sun YH, Zhang XW, Wu XM, Gao XB, Li TX | title = New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China | journal = Journal of Virology | volume = 79 | issue = 24 | pages = 15460–15466 | date = December 2005 | pmid = 16306617 | pmc = 1316012 | doi = 10.1128/JVI.79.24.15460-15466.2005 }}{{cite journal | vauthors = ((The World Health Organization Global Influenza Program Surveillance Network)) | title = Evolution of H5N1 avian influenza viruses in Asia | journal = Emerging Infectious Diseases | volume = 11 | issue = 10 | pages = 1515–1521 | date = October 2005 | pmid = 16318689 | pmc = 3366754 | doi = 10.3201/eid1110.050644 }} Figure 1 shows a diagramatic representation of the genetic relatedness of Asian H5N1 hemagglutinin genes from various isolates of the virus With reassortment between strains, an avian strain which does not affect humans may acquire characteristics from a different strain which enable it to infect and pass between humans – a zoonotic event.{{Cite web |date=15 May 2024 |title=Transmission of Bird Flu Viruses Between Animals and People |url=https://www.cdc.gov/flu/avianflu/virus-transmission.htm |access-date=10 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }} It is thought that all influenza A viruses causing outbreaks or pandemics among humans since the 1900s originated from strains circulating in wild aquatic birds through reassortment with other influenza strains.{{cite journal | vauthors = Taubenberger JK, Morens DM | title = Influenza: the once and future pandemic | journal = Public Health Reports | volume = 125 | issue = Suppl 3 | pages = 16–26 | date = April 2010 | pmid = 20568566 | pmc = 2862331 | doi = 10.1177/00333549101250S305 }}{{cite journal | vauthors = Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y | title = Evolution and ecology of influenza A viruses | journal = Microbiological Reviews | volume = 56 | issue = 1 | pages = 152–179 | date = March 1992 | pmid = 1579108 | pmc = 372859 | doi = 10.1128/mr.56.1.152-179.1992 }} It is possible (though not certain) that pigs may act as an intermediate host for reassortment.{{Cite web |date=15 June 2017 |title=Factsheet on swine influenza in humans and pigs |url=https://www.ecdc.europa.eu/en/swine-influenza/factsheet |access-date=13 June 2024 |website=European Centre for Disease Control }}

The Global Influenza Surveillance and Response System (GISRS) is a global network of laboratories that monitor the spread of influenza with the aim to provide the World Health Organization with influenza control information and to inform vaccine development. Several millions of specimens are tested by the GISRS network annually through a network of laboratories in 127 countries. As well as human viruses, GISRS also monitors avian, swine, and other potentially zoonotic influenza viruses.

{{Main|Flu season}}

File:CDC-influenza-pneumonia-deaths-2015-01-10.gif

Flu season is an annually recurring time period characterized by the prevalence of an outbreak of influenza, caused either by Influenza A or by Influenza B. The season occurs during the cold half of the year in temperate regions; November through February in the northern hemisphere and May to October in the southern hemisphere. Flu seasons also exist in the tropics and subtropics, with variability from region to region.{{cite journal | vauthors = Hirve S, Newman LP, Paget J, Azziz-Baumgartner E, Fitzner J, Bhat N, Vandemaele K, Zhang W | title = Influenza Seasonality in the Tropics and Subtropics – When to Vaccinate? | journal = PLOS ONE | volume = 11 | issue = 4 | pages = e0153003 | date = 27 April 2016 | pmid = 27119988 | pmc = 4847850 | doi = 10.1371/journal.pone.0153003 | doi-access = free | bibcode = 2016PLoSO..1153003H }} Annually, about 3 to 5 million cases of severe illness and 290,000 to 650,000 deaths from seasonal flu occur worldwide.

There are several possible reasons for the winter peak in temperate regions:

• During the winter, people spend more time indoors with the windows sealed, so they are more likely to breathe the same air as someone who has the flu and thus contract the virus.{{Cite web |date=1 December 2014 |title=The Reason for the Season: why flu strikes in winter |url=https://sitn.hms.harvard.edu/flash/2014/the-reason-for-the-season-why-flu-strikes-in-winter/ |access-date=21 June 2024 |website=Science in the News, a Graduate Student Group at the Harvard Graduate School of the Arts and Sciences. }}
• Days are shorter during the winter, and lack of sunlight leads to low levels of vitamin D and melatonin, both of which require sunlight for their generation. This compromises our immune systems, which in turn decreases ability to fight the virus.
• The influenza virus may survive better in colder, drier climates, and therefore be able to infect more people.
• Cold air reduces the ability of the nasal membranes to resist infection.{{Cite web | vauthors = LaMotte S |date=6 December 2022 |title=Scientists finally know why people get more colds and flu in winter |url=https://www.cnn.com/2022/12/06/health/why-winter-colds-flu-wellness/index.html |access-date=21 June 2024 |website=CNN }}

A zoonosis a disease in a human caused by a pathogen (such as a bacterium, or virus) that has jumped from a non-human to a human.{{cite Merriam-Webster|zoonosis|access-date=29 March 2019}}{{Cite web |date=29 July 2020 |title=Zoonoses - Key Facts |url=https://www.who.int/news-room/fact-sheets/detail/zoonoses |access-date=24 June 2024 |website=World Health Organization }} Avian and pig influenza viruses can, on rare occasions, transmit to humans and cause zoonotic influenza virus infections; these infections are usually confined to people who have been in close contact with infected animals or material such as infected feces and meat, they do not spread to other humans. Symptoms of these infections in humans vary greatly; some are in asymptomatic or mild while others can cause severe disease, leading to severe pneumonia and death.{{Cite web |date=23 May 2023 |title=Zoonotic influenza - Annual Epidemiological Report for 2022 |url=https://www.ecdc.europa.eu/en/publications-data/zoonotic-influenza-annual-epidemiological-report-2022 |access-date=24 June 2024 |website=www.ecdc.europa.eu }} A wide range of Influenza A virus subtypes have been found to cause zoonotic disease.{{Cite web |date=29 July 2020 |title=Global AIV with Zoonotic Potential |url=https://www.fao.org/animal-health/situation-updates/global-aiv-with-zoonotic-potential/en |access-date=24 June 2024 |website=The Food and Agriculture Organization (FAO) of the United Nations }}

Zoonotic infections can be prevented by good hygiene, by preventing farmed animals from coming into contact with wild animals, and by using appropriate personal protective equipment.

As of June 2024, there is concern about two subtypes of avian influenza which are circulating in wild bird populations worldwide, H5N1 and H7N9. Both of these have potential to devastate poultry stocks, and both have jumped to humans with relatively high case fatality rates. H5N1 in particular has infected a wide range of mammals and may be adapting to mammalian hosts.{{cite journal | vauthors = Plaza PI, Gamarra-Toledo V, Euguí JR, Lambertucci SA | title = Recent Changes in Patterns of Mammal Infection with Highly Pathogenic Avian Influenza A(H5N1) Virus Worldwide | journal = Emerging Infectious Diseases | volume = 30 | issue = 3 | pages = 444–452 | date = March 2024 | pmid = 38407173 | pmc = 10902543 | doi = 10.3201/eid3003.231098 }}

{{Main|Influenza vaccine}}

As of June 2024, the influenza viruses which circulate widely in humans are IAV subtypes H1N1 and H3N2, together with Influenza B.{{Cite web |date=30 March 2023 |title=Types of Influenza Viruses |url=https://www.cdc.gov/flu/about/viruses/types.htm |access-date=22 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }} Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.{{cite journal | vauthors = Chow EJ, Doyle JD, Uyeki TM | title = Influenza virus-related critical illness: prevention, diagnosis, treatment | journal = Critical Care | volume = 23 | issue = 1 | pages = 214 | date = June 2019 | pmid = 31189475 | pmc = 6563376 | doi = 10.1186/s13054-019-2491-9 | doi-access = free }} Vaccines against the flu are trivalent or quadrivalent, providing protection against the dominant strains of IAV(H1N1) and IAV(H3N2), and one or two influenza B virus strains; the formulation is continually reviewed in order to match the predominant strains in circulation.{{cite journal | vauthors = Dharmapalan D | title = Influenza | journal = Indian Journal of Pediatrics | volume = 87 | issue = 10 | pages = 828–832 | date = October 2020 | pmid = 32048225 | pmc = 7091034 | doi = 10.1007/s12098-020-03214-1 }}{{cite journal | vauthors = Sautto GA, Kirchenbaum GA, Ross TM | title = Towards a universal influenza vaccine: different approaches for one goal | journal = Virology Journal | volume = 15 | issue = 1 | pages = 17 | date = January 2018 | pmid = 29370862 | pmc = 5785881 | doi = 10.1186/s12985-017-0918-y | doi-access = free }}

It is possible to vaccinate poultry and pigs against specific strains of influenza. Vaccination should be combined with other control measures such as infection monitoring, early detection and biosecurity.{{Cite web |date=10 October 2023 |title=Vaccination of poultry against highly pathogenic avian influenza – Available vaccines and vaccination strategies |url=https://www.efsa.europa.eu/en/news/vaccination-poultry-against-highly-pathogenic-avian-influenza-available-vaccines-and |access-date=9 May 2024 |website=efsa.europa.eu |publisher= }}{{Cite web |date=3 June 2024 |title=Making a Candidate Vaccine Virus (CVV) for a HPAI (Bird Flu) Virus |url=https://www.cdc.gov/bird-flu/php/severe-potential/candidate-vaccine-virus.html |access-date=15 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }}{{Cite web |date=19 October 2023 |title=What People Who Raise Pigs Need To Know About Influenza (Flu) |url=https://www.cdc.gov/flu/swineflu/people-raise-pigs-flu.htm |access-date=22 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }}

{{Main|Influenza treatment}}

The main treatment for mild influenza is supportive; rest, fluids, and over-the-counter medicines to alleviate symptoms while the body's own immune system works to recover from infection. Antiviral drugs are recommended for those with severe symptoms, or for those who are at risk of developing complications such as pneumonia.{{Cite web |date=22 March 2024 |title=Take everyday precautions to protect others while sick |url=https://t.cdc.gov/2S4E |access-date=22 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }}{{Cite web |title=Influenza (Seasonal) |url=https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal) |access-date=22 June 2024 |website=World Health Organization }}

{{Main|Influenza}}

File:Symptoms_of_influenza.svg (CDC)}}{{cite web |date=26 February 2019 |title=Flu Symptoms & Complications |url=https://www.cdc.gov/flu/symptoms/symptoms.htm |url-status=live |archive-url=https://web.archive.org/web/20200801071343/https://www.cdc.gov/flu/symptoms/symptoms.htm |archive-date=1 August 2020 |access-date=6 July 2019 |website=U.S. Centers for Disease Control and Prevention}} with fever and cough the most common symptoms{{cite journal | vauthors = Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP | title = Does this patient have influenza? | journal = JAMA | volume = 293 | issue = 8 | pages = 987–997 | date = February 2005 | pmid = 15728170 | doi = 10.1001/jama.293.8.987 }}]]

The symptoms of seasonal flu are similar to those of a cold, although usually more severe and less likely to include a runny nose.{{Cite web |date=29 September 2022 |title=Cold Versus Flu |url=https://www.cdc.gov/flu/symptoms/coldflu.htm |access-date=25 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }} The onset of symptoms is sudden, and initial symptoms are predominately non-specific: a sudden fever; muscle aches; cough; fatigue; sore throat; headache; difficulty sleeping; loss of appetite; diarrhoea or abdominal pain; nausea and vomiting.{{Cite web |date=9 August 2023 |title=Flu |url=https://www.nhs.uk/conditions/flu/ |access-date=25 June 2024 |website=National Health Service UK }}

Humans can rarely become infected with strains of avian or swine influenza, usually as a result of close contact with infected animals or contaminated material; symptoms generally resemble seasonal flu but occasionally can be severe, including death.

{{Main|Avian influenza}}

Some species of wild aquatic birds act as natural asymptomatic carriers of a large variety of influenza A viruses, which they can spread over large distances in their annual migration.{{Cite web |date=13 December 2022 |title=Bird flu (avian influenza): how to spot and report it in poultry or other captive birds |url=https://www.gov.uk/guidance/avian-influenza-bird-flu |access-date=6 May 2024 |website=Department for Environment, Food & Rural Affairs and Animal and Plant Health Agency }} Symptoms of avian influenza vary according to both the strain of virus underlying the infection, and on the species of bird affected. Symptoms of influenza in birds may include swollen head, watery eyes, unresponsiveness, lack of coordination, respiratory distress such as sneezing or gurgling.{{Cite web |title=Avian flu |url=https://rspb.org.uk/birds-and-wildlife/avian-influenza-updates |access-date=25 June 2024 |website=The Royal Society for the Protection of Birds (RSPB)}}

Because of the impact of avian influenza on economically important chicken farms, avian virus strains are classified as either highly pathogenic (and therefore potentially requiring vigorous control measures) or low pathogenic. The test for this is based solely on the effect on chickens - a virus strain is highly pathogenic avian influenza if 75% or more of chickens die after being deliberately infected with it, or if it is genetically similar to such a strain. The alternative classification is low pathogenic avian influenza.{{cite journal | vauthors = Alexander DJ, Brown IH | title = History of highly pathogenic avian influenza | journal = Revue Scientifique et Technique | volume = 28 | issue = 1 | pages = 19–38 | date = April 2009 | pmid = 19618616 | doi = 10.20506/rst.28.1.1856 | doi-access = }} Classification of a virus strain as either a low or high pathogenic strain is based on the severity of symptoms in domestic chickens and does not predict severity of symptoms in other species. Chickens infected with low pathogenic avian influenza display mild symptoms or are asymptomatic, whereas highly pathogenic avian influenza causes serious breathing difficulties, significant drop in egg production, and sudden death.{{Cite web |date=14 June 2022 |title=Avian Influenza in Birds |url=https://www.cdc.gov/flu/avianflu/avian-in-birds.htm |access-date=6 May 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }}

Since 2006, the World Organization for Animal Health requires all detections of low pathogenic avian influenza H5 and H7 subtypes to be reported because of their potential to mutate into highly pathogenic strains.{{Cite web |date=October 2013 |title=National H5/H7 Avian Influenza surveillance plan |url=https://www.aphis.usda.gov/media/document/1295/file |website=United States Department of Agriculture |publisher=Animal Plant Health Inspection Service}}

{{Main|Swine influenza}}

Signs of swine flu in pigs can include fever, depression, coughing (barking), discharge from the nose or eyes, sneezing, breathing difficulties, eye redness or inflammation, and going off feed. Some pigs infected with influenza, however, may show no signs of illness at all. Swine flu subtypes are principally H1N1, H1N2, and H3N2;{{Cite web |date=15 June 2017 |title=Factsheet on swine influenza in humans and pigs |url=https://www.ecdc.europa.eu/en/swine-influenza/factsheet |access-date=25 June 2024 |website=European Centre for Disease Prevention and Control }} it is spread either through close contact between animals or by the movement of contaminated equipment between farms.{{Cite web |date=3 October 2018 |title=Key Facts about Swine Influenza (Swine Flu) in Pigs |url=https://www.cdc.gov/flu/swineflu/keyfacts_pigs.htm |access-date=25 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }} Humans who are in close contact with pigs can sometimes become infected.{{Cite web |date=30 March 2024 |title=2023: outbreaks of swine influenza |url=https://www.who.int/news/item/30-03-2024-2023--outbreaks-of-swine-influenza |access-date=25 June 2024 |website=World Health Organization }}

{{Main|Equine influenza}}

Equine influenza can affect horses, donkeys, and mules;{{Cite web |title=Equine influenza |url=https://www.woah.org/en/disease/equine-influenza-2/ |access-date=25 June 2024 |website=WOAH – World Organisation for Animal Health }} it has a very high rate of transmission among horses, and a relatively short incubation time of one to three days.{{Cite web |title=Equine Influenza: Respiratory Diseases of Horses: Merck Veterinary Manual |url=http://www.merckvetmanual.com/mvm/respiratory_system/respiratory_diseases_of_horses/equine_influenza.html |url-status=dead |archive-url=https://web.archive.org/web/20161115191119/http://www.merckvetmanual.com/mvm/respiratory_system/respiratory_diseases_of_horses/equine_influenza.html |archive-date=15 November 2016 |access-date=4 December 2016 |website=www.merckvetmanual.com}} Clinical signs of equine influenza include fever, nasal discharge, have a dry, hacking cough, depression, loss of appetite and weakness. EI is caused by two subtypes of influenza A viruses: H7N7 and H3N8, which have evolved from avian influenza A viruses.{{Cite web |date=5 May 2023 |title=Horse Flu |url=https://www.cdc.gov/flu/other/horse-flu-faq.htm |access-date=25 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }}

{{Main|Canine influenza}}

Most animals infected with canine influenza A will show symptoms such as coughing, runny nose, fever, lethargy, eye discharge, and a reduced appetite lasting anywhere from 2–3 weeks. There are two different influenza A dog flu viruses: one is an H3N8 virus and the other is an H3N2 virus.{{Cite web |date=29 August 2023 |title=Key Facts about Canine Influenza (Dog Flu) |url=https://www.cdc.gov/flu/other/canine-flu/keyfacts.html |access-date=25 June 2024 |website=U.S. Centers for Disease Control and Prevention (CDC) }} The H3N8 strain has evolved from an equine influenza avian virus which has adapted to sustained transmission among dogs. The H3N2 strain is derived from an avian influenza which jumped to dogs in 2004 in either Korea or China. It is likely that the virus persists in both animal shelters and kennels, as well as in farms where dogs are raised for meat production.{{cite journal | vauthors = Wasik BR, Voorhees IE, Parrish CR | title = Canine and Feline Influenza | journal = Cold Spring Harbor Perspectives in Medicine | volume = 11 | issue = 1 | pages = a038562 | date = January 2021 | pmid = 31871238 | pmc = 7778219 | doi = 10.1101/cshperspect.a038562 }}

{{Main|Bat influenza}}

The first bat flu virus, IAV(H17N10), was first discovered in 2009 in little yellow-shouldered bats (Sturnira lilium) in Guatemala.{{cite web |title=Bat Influenza (Flu) |url=https://www.cdc.gov/flu-in-animals/about/bat-flu.html |access-date=23 March 2025 |website=cdc.gov}} In 2012 a second bat influenza A virus IAV(H18N11) was discovered in flat-faced fruit-eating bats (Artibeus planirostris) from Peru.{{cite web |title=Characterization of bat influenza viruses |url=https://www.uniklinik-freiburg.de/virologie-en/research/research-teams/martin-schwemmle-team/bat-influenza-viruses.html |access-date=30 June 2020 |website=uniklinik-freiburg.de}}{{cite journal |date=2013 |title=New flu virus found in bats |url=https://www.nature.com/articles/503169e |journal=Nature |volume=503 |issue=7475 |page=169 |doi=10.1038/503169e |access-date=30 June 2020}}{{cite journal | vauthors = Ciminski K, Pfaff F, Beer M, Schwemmle M | title = Bats reveal the true power of influenza A virus adaptability | journal = PLOS Pathogens | volume = 16 | issue = 4 | pages = e1008384 | date = April 2020 | pmid = 32298389 | pmc = 7161946 | doi = 10.1371/journal.ppat.1008384 | doi-access = free }} Bat influenza viruses have been found to be poorly adapted to non-bat species.{{cite journal | vauthors = Ciminski K, Ran W, Gorka M, Lee J, Malmlov A, Schinköthe J, Eckley M, Murrieta RA, Aboellail TA, Campbell CL, Ebel GD, Ma J, Pohlmann A, Franzke K, Ulrich R, Hoffmann D, García-Sastre A, Ma W, Schountz T, Beer M, Schwemmle M | title = Bat influenza viruses transmit among bats but are poorly adapted to non-bat species | journal = Nature Microbiology | volume = 4 | issue = 12 | pages = 2298–2309 | date = December 2019 | pmid = 31527796 | pmc = 7758811 | doi = 10.1038/s41564-019-0556-9 | s2cid = 202580293 }}

Influenza research includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and why some influenza viruses are deadlier than others.{{cite web |date=13 March 2017 |title=Influenza Basic Research |url=https://www.niaid.nih.gov/diseases-conditions/influenza-basic-research |url-status=live |archive-url=https://web.archive.org/web/20240610052845/https://www.niaid.nih.gov/diseases-conditions/influenza-basic-research |archive-date=10 June 2024 |access-date=24 March 2021 |publisher=National Institute of Allergy and Infectious Diseases}} Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand and prevent flu pandemics.{{cite journal | vauthors = Potter CW | title = A history of influenza | journal = Journal of Applied Microbiology | volume = 91 | issue = 4 | pages = 572–579 | date = October 2001 | pmid = 11576290 | doi = 10.1046/j.1365-2672.2001.01492.x | s2cid = 26392163 }}{{cite journal | vauthors = Taubenberger JK, Baltimore D, Doherty PC, Markel H, Morens DM, Webster RG, Wilson IA | title = Reconstruction of the 1918 influenza virus: unexpected rewards from the past | journal = mBio | volume = 3 | issue = 5 | date = November 2012 | pmid = 22967978 | pmc = 3448162 | doi = 10.1128/mBio.00201-12 }}

The World Health Organization has published a Research Agenda with five streams:{{Cite web |date=2017 |title=WHO public health research agenda for influenza: 2017 update |url=https://www.who.int/initiatives/public-health-research-agenda-for-influenza |access-date=28 June 2024 |website=World Health Organization |place=Geneva }}

• Stream 1. Reducing the risk of emergence of pandemic influenza. This stream is entirely focused on preventing and limiting pandemic influenza; this includes research into what characteristics make a strain either mild or deadly, worldwide surveillance of influenza A viruses with pandemic potential, and the prevention and management of potentially zoonotic influenza in domestic and farmed animals.
• Stream 2. Limiting the spread of pandemic, zoonotic and seasonal epidemic influenza. This is more broadly targeted at both pandemic and seasonal influenza, looking at the transmission of the virus between people and the ways in which it can spread globally, as well as the environmental and social factors which affect transmission.
• Stream 3. Minimizing the impact of pandemic, zoonotic, and seasonal epidemic influenza. This is principally concerned with vaccination – improving the effectiveness of vaccines, vaccine technology, as well as the speed with which an effective vaccine can be developed and ways in which vaccines can be manufactured and delivered worldwide.
• Stream 4. Optimizing the treatment of patients. This stream aims to reduce the impact of influenza by looking at methods of treatment, vulnerable groups, genetic predispositions, the interaction of influenza infection with other diseases, and influenza sequelae.
• Stream 5. Promoting the development and application of modern public health tools. Aiming to improve the ways in which public policy can combat influenza; this includes the introduction of new technologies, epidemic and pandemic modelling, and the communication of accurate and trustworthy information to the public.

• Influenza vaccine
• Veterinary virology

{{Reflist|30em}}

;Official sources

{{Further|H5N1}}

• [https://www.cdc.gov/flu/pandemic-resources/index.htm Pandemic Influenza] US CDC

;General information

{{Further|Flu}}

• [http://www.nature.com/nature/focus/avianflu/index.html Web focus: Warnings of a Flu Pandemic] Nature
• [http://www.nature.com/avianflu/index.html Nature Reports: Homepage: Avian Flu]
• {{cite journal | vauthors = Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY | title = Avian influenza A (H5N1) infection in humans | journal = The New England Journal of Medicine | volume = 353 | issue = 13 | pages = 1374–1385 | date = September 2005 | pmid = 16192482 | doi = 10.1056/NEJMra052211 | citeseerx = 10.1.1.730.7890 }}
• [https://digital.library.unt.edu/govdocs/crs/permalink/meta-crs-7927 Pandemic Influenza: Domestic Preparedness Efforts] Congressional Research Service Report on Pandemic Preparedness.
• {{cite book |last=Mahmoud |title=The threat of pandemic influenza : are we ready? : workshop summary / prepared for Forum on Microbial Threats, Board on Global Health |editor=Stacey L. Knobler |editor2=Alison Mack |editor3-first=Adel |editor3-last=Mahmoud |editor4=Stanley M. Lemon |isbn=0-309-09504-2 |publisher=The National Academies Press |year=2005 |page=285 |quote=Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents}}
• {{cite book |last1=Mahmoud |first1=Adel A. F |author2=Institute of Medicine | last3 = Knobler | first3 = Stacey | last4 = Mack | first4 = Alison |title=The Threat of Pandemic Influenza: Are We Ready?: Workshop Summary |publisher=National Academies Press |location=Washington, D.C. |year=2005 |isbn=978-0-309-09504-4 |url=http://www.nap.edu/openbook.php?record_id=11150&page=R1}}
• [http://www.lib.uiowa.edu/hardin/md/birdflu.html Links to Bird Flu pictures (Hardin MD/Univ of Iowa)] {{Webarchive|url=https://web.archive.org/web/20101115190436/http://www.lib.uiowa.edu/hardin/md/birdflu.html |date=15 November 2010 }}
• {{cite book | vauthors = Kawaoka Y |title=Influenza Virology: Current Topics |publisher=Caister Academic Pr |year=2006 |isbn=978-1-904455-06-6 }}
• {{cite book | vauthors = Sobrino F, Mettenleiter T |title=Animal Viruses: Molecular Biology |publisher=Caister Academic Press |year=2008 |isbn=978-1-904455-22-6 }}

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