View source for Orthomyxoviridae

{{Short description|Family of RNA viruses including the influenza viruses}}
{{About|the virus family that contains seven genera|specific information about the subfamily that affects humans|Influenza}}
{{Virusbox
| taxon = Orthomyxoviridae
| image = Fimmu-09-01581-g001.jpg
| image_caption = [[Influenza A virus|Influenza A]] and [[Influenza B virus|influenza B]] viruses genome, mRNA, and virion diagram
| subdivision_ranks = Genera
| subdivision = [[#Classification|See text]]
}}

'''''Orthomyxoviridae''''' ({{etymology|grc|''ὀρθός'' (orthós)|straight||''μύξα'' (mýxa)|mucus}})<ref>[https://web.archive.org/web/20010219135337/http://www4.ncbi.nlm.nih.gov/ICTVdb/Ictv/fs_ortho.htm International Committee on Taxonomy of Viruses] Index of Viruses — Orthomyxovirus (2006). In: ICTVdB—The Universal Virus Database, version 4. Büchen-Osmond, C (Ed), Columbia University, New York.</ref> is a family of [[negative-sense single-stranded RNA virus|negative-sense]] [[RNA virus]]es. It includes nine [[genus|genera]]: ''[[Influenza A virus|Alphainfluenzavirus]]'', ''[[Influenza B virus|Betainfluenzavirus]]'', ''[[Influenza C virus|Gammainfluenzavirus]]'', ''[[Influenza D virus|Deltainfluenzavirus]]'',  ''[[Isavirus]]'', ''[[Mykissvirus]]'',  ''[[Quaranjavirus]]'', ''[[Sardinovirus]]'', and ''[[Thogotovirus]]''. The first four genera contain viruses that cause [[influenza]] in [[bird]]s (see also [[avian influenza]]) and [[mammal]]s, including humans. Isaviruses infect [[salmon]]; the thogotoviruses are [[arbovirus]]es, infecting [[vertebrate]]s and [[invertebrate]]s (such as [[tick]]s and [[mosquito]]es).<ref name="pmid2617637">{{cite journal |vauthors=Jones LD, Nuttall PA |title=Non-viraemic transmission of Thogoto virus: influence of time and distance |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=83 |issue=5 |pages=712–14 |year=1989 |pmid=2617637 |doi=10.1016/0035-9203(89)90405-7}}</ref><ref>{{cite web |url=http://www.nimr.mrc.ac.uk/MillHillEssays/1999/isa.htm |title=Infectious Salmon Anaemia |access-date=2007-09-14 |first=Barry |last=Ely |name-list-style=vanc |year=1999 |work=Mill Hill Essays |publisher=[[National Institute for Medical Research]] |archive-url=https://web.archive.org/web/20070824184945/http://www.nimr.mrc.ac.uk/MillHillEssays/1999/isa.htm |archive-date=2007-08-24}}</ref><ref name="pmid11678233">{{cite journal |vauthors=Raynard RS, Murray AG, Gregory A |title=Infectious salmon anaemia virus in wild fish from Scotland |journal=Dis. Aquat. Org. |volume=46 |issue=2 |pages=93–100 |year=2001 |pmid=11678233 |doi=10.3354/dao046093|doi-access=free }}</ref> The Quaranjaviruses are also [[arbovirus]]es, infecting vertebrates (birds) and invertebrates ([[arthropod]]s).

The four genera of Influenza virus that infect vertebrates, which are identified by antigenic differences in their [[nucleoprotein]] and [[matrix protein]], are as follows:
* ''[[Influenza A virus|Alphainfluenzavirus]]'' infects humans, other mammals, and birds, and causes all [[flu pandemic]]s
* ''[[Influenza B virus|Betainfluenzavirus]]'' infects humans and [[pinniped|seals]]
* ''[[Influenza C virus|Gammainfluenzavirus]]'' infects humans and [[pig]]s
* ''[[Influenza D virus|Deltainfluenzavirus]]'' infects pigs and [[cattle]].

== Structure ==
[[File:Viruses-10-00497-g001.png|thumb|Influenza A virus structure]]
The influenzavirus [[Virus|virion]] is [[Pleomorphism (microbiology)|pleomorphic]]; the [[viral envelope]] can occur in spherical and filamentous forms. In general, the virus's morphology is ellipsoidal with particles 100–120&nbsp;[[nanometer|nm]] in diameter, or filamentous with particles 80–100&nbsp;nm in diameter and up to 20&nbsp;μm long.<ref>{{cite journal | vauthors = Noda T | title = Native morphology of influenza virions | journal = Frontiers in Microbiology | volume = 2 | page = 269 | date = 2012-01-03 | pmid = 22291683 | pmc = 3249889 | doi = 10.3389/fmicb.2011.00269 | doi-access = free }}</ref> There are approximately 500 distinct spike-like surface projections in the envelope each projecting 10–14&nbsp;nm from the surface with varying surface densities. The major [[glycoprotein]] (HA) spike is interposed irregularly by clusters of [[neuraminidase]] (NA) spikes, with a ratio of HA to NA of about 10 to 1.<ref>{{cite journal | vauthors = Einav T, Gentles LE, Bloom JD | title = SnapShot: Influenza by the Numbers | journal = Cell | volume = 182 | issue = 2 | pages = 532–532.e1 | date = 2020-07-23 | doi = 10.1016/j.cell.2020.05.004 | pmid = 32707094 | s2cid = 220715148 | url = https://www.cell.com/cell/pdf/S0092-8674(20)30566-3.pdf }}</ref>

The viral envelope composed of a [[lipid bilayer]] membrane in which the glycoprotein spikes are anchored encloses the [[capsids|nucleocapsids]]; nucleoproteins of different sizes; the arrangement within the virion is uncertain. The ribonuclear proteins are filamentous and fall in the range of 50–150&nbsp;nm long with helical symmetry.<ref name=ictvreport />

== Genome ==
{{For|an in-depth example|H5N1 genetic structure}}
[[File:DOI_10.5772_55289_image1_w.jpg|thumb|Illustration of influenza virus replication and genome. A) Replication and transcription of influenza A virus. B) Influenza A genome. C) Influenza B genome.  D) Influenza C genome. Segments translate to [[RNA-dependent RNA polymerase|polymerase]] (PB1, PB2, and PA), [[Hemagglutinin (influenza)|hemagglutinin]] (HA), [[Neuraminidase|neuramindase]] (NA), [[nucleoprotein]] (NP), membrane protein (M), and [[Viral nonstructural protein|non-structural protein]] (NS).]]
Viruses of the family ''Orthomyxoviridae'' contain six to eight segments of linear [[Sense (molecular biology)|negative-sense]] single stranded RNA. They have a total genome length that is 10,000–14,600 [[nucleotide]]s (nt).<ref name=ictvreport >{{cite web|url=https://ictv.global/report_9th/RNAneg/Orthomyxoviridae|title=ICTV Ninth Report; 2009 Taxonomy Release: ''Orthomyxoviridae''|author=<!--Not stated-->|website=ICTV|access-date=19 September 2020}}</ref> The influenza A [[genome]], for instance, has eight pieces of segmented negative-sense [[RNA]] (13.5 kilobases total).<ref name="Ghedin">{{cite journal|vauthors=Ghedin E, Sengamalay NA, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro DJ, Sitz J, Koo H, Bolotov P, Dernovoy D, Tatusova T, Bao Y, St George K, Taylor J, Lipman DJ, Fraser CM, Taubenberger JK, Salzberg SL|date=October 2005|title=Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution|journal=Nature|volume=437|issue=7062|pages=1162–6|bibcode=2005Natur.437.1162G|doi=10.1038/nature04239|pmid=16208317|doi-access=free}}</ref>

The best-characterised of the influenzavirus proteins are [[hemagglutinin]] and [[neuraminidase]], two large [[glycoprotein]]s found on the outside of the viral particles. Hemagglutinin is a [[lectin]] that mediates binding of the virus to target cells and entry of the viral genome into the target cell.<ref>{{cite journal|vauthors=Suzuki Y|date=March 2005|title=Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses|journal=Biological & Pharmaceutical Bulletin|volume=28|issue=3|pages=399–408|doi=10.1248/bpb.28.399|pmid=15744059|doi-access=free}}</ref> In contrast, neuraminidase is an [[enzyme]] involved in the release of [[Offspring|progeny]] virus from infected cells, by cleaving sugars that bind the mature viral particles. The hemagglutinin (H) and neuraminidase (N) [[protein]]s are key targets for antibodies and antiviral drugs,<ref name="Hilleman">{{cite journal|vauthors=Hilleman MR|date=August 2002|title=Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control|journal=Vaccine|volume=20|issue=25–26|pages=3068–87|doi=10.1016/S0264-410X(02)00254-2|pmid=12163258}}</ref><ref>{{cite journal|vauthors=Wilson JC, von Itzstein M|date=July 2003|title=Recent strategies in the search for new anti-influenza therapies|journal=Current Drug Targets|volume=4|issue=5|pages=389–408|doi=10.2174/1389450033491019|pmid=12816348}}</ref> and they are used to classify the different [[serotype]]s of influenza A viruses, hence the ''H'' and ''N'' in ''H5N1''.

The genome sequence has terminal repeated sequences, and these are repeated at both ends (i.e., at both the 5’ end and the 3’ end). These terminal repeats at the 5′-end are 12–13 nucleotides long. Nucleotide sequences at the 3′-terminus are identical, are the same in genera of the same family, most on RNA (segments), or on all RNA species. Terminal repeats at the 3′-end are 9–11 nucleotides long. Encapsidated nucleic acid is solely genomic. Each virion may contain defective interfering copies. In Influenza A (specifically, in H1N1) PB1-F2 is produced from an alternative reading frame in PB1. The M and NS genes produce two genes each (4 genes total) via [[alternative splicing]].<ref name="Bouvier2008">{{cite journal|vauthors=Bouvier NM, Palese P|date=September 2008|title=The biology of influenza viruses|journal=Vaccine|volume=26|issue=Suppl 4 |pages=D49–53|doi=10.1016/j.vaccine.2008.07.039|pmc=3074182|pmid=19230160}}</ref>

== Replication cycle ==
[[File:Virus Replication.svg|thumb|right|Infection and replication of the influenza virus. The steps in this process are discussed in the text.]]

Typically, influenza is transmitted from infected mammals through the air by coughs or sneezes, creating [[particulate|aerosols]] containing the virus, and from infected birds through their [[feces|droppings]]. Influenza can also be transmitted by [[saliva]], [[mucus|nasal secretions]], [[feces]] and [[blood]]. Infections occur through contact with these bodily fluids or with contaminated surfaces. On certain surfaces (i.e, outside of a host), flu viruses can remain infectious for about one week at human body temperature, over 30 days at {{convert|0|°C}}, and indefinitely at very low temperatures (such as in lakes in northeast [[Siberia]]). They can be inactivated easily by [[disinfectant]]s and [[detergent]]s.<ref>{{cite journal | vauthors = Suarez DL, Spackman E, Senne DA, Bulaga L, Welsch AC, Froberg K | title = The effect of various disinfectants on detection of avian influenza virus by real time RT-PCR | journal = Avian Diseases | volume = 47 | issue = 3 Suppl | pages = 1091–5 | year = 2003 | pmid = 14575118 | doi = 10.1637/0005-2086-47.s3.1091 | s2cid = 8612187 }}</ref><ref>{{cite web | url = http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/biofacts/avflu_human.html | title = Avian Influenza (Bird Flu) Implications for Human Disease. Physical characteristics of influenza A viruses. | work = CIDRAP - Center for Infectious Disease Research and Policy | date = 12 March 2024 | publisher = University of Minnesota }}</ref><ref name="NHZ2006-11-30">{{cite news |url=http://www.nzherald.co.nz/health/news/article.cfm?c_id=204&objectid=10413124 |title=Flu viruses 'can live for decades' on ice |date=November 30, 2006 |agency=[[Reuters]] |work=[[The New Zealand Herald]] |access-date=November 1, 2011}}</ref>

The viruses interacts between its surface [[hemagglutinin]] glycoprotein to bind to the host's surface [[sialic acid]] sugars, specifically on the surfaces of [[epithelium|epithelial cells]] in the lung and throat (Stage 1 in infection figure).<ref name=Wagner>{{cite journal |vauthors=Wagner R, Matrosovich M, Klenk H | title = Functional balance between haemagglutinin and neuraminidase in influenza virus infections | journal = Rev Med Virol | volume = 12 | issue = 3 | pages = 159–66 |date=May–Jun 2002| pmid = 11987141 | doi = 10.1002/rmv.352| s2cid = 30876482 }}</ref> The cell imports the virus by [[endocytosis]]. In the acidic pH environment of the [[endosome]], part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, releasing: the viral RNA (vRNA) molecules, accessory proteins and [[RNA replicase|RNA-dependent RNA polymerase]] into the host cell's [[cytoplasm]] (Stage 2).<ref>{{cite journal |vauthors=Lakadamyali M, Rust M, Babcock H, Zhuang X | title = Visualizing infection of individual influenza viruses | journal = Proc Natl Acad Sci USA | volume = 100 | issue = 16 | pages = 9280–85 | date=Aug 5, 2003 | pmid = 12883000 | doi = 10.1073/pnas.0832269100 | pmc = 170909|bibcode = 2003PNAS..100.9280L | doi-access = free }}</ref> These proteins and vRNA form a complex that is transported into the host [[cell nucleus]], where the host's own RNA-dependent RNA polymerase begins transcribing complementary positive-sense cRNA (Steps 3a and b).<ref>{{cite journal |vauthors=Cros J, Palese P | title = Trafficking of viral genomic RNA into and out of the nucleus: influenza, Thogoto and Borna disease viruses | journal = Virus Res | volume = 95 | issue = 1–2 | pages = 3–12 |date=September 2003 | pmid = 12921991 | doi = 10.1016/S0168-1702(03)00159-X}}</ref> The cRNA is either exported into the cytoplasm and translated (step 4), or remains in the host nucleus. Newly synthesised viral proteins are either secreted through the [[Golgi apparatus]] onto the host cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported into the host nucleus, where they bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular [[mRNA]] and using those consequently-released [[nucleotide]]s for vRNA synthesis, while also inhibiting translation of the host cell's mRNAs.<ref>{{cite journal |vauthors=Kash J, Goodman A, Korth M, Katze M | title = Hijacking of the host-cell response and translational control during influenza virus infection | journal = Virus Res | volume = 119 | issue = 1 | pages = 111–20 |date=July 2006 | pmid = 16630668 | doi = 10.1016/j.virusres.2005.10.013}}</ref>

A virion assembles from negative-sense vRNAs (that form the [[genome]]s of newly created viruses), RNA-dependent RNA transcriptase and other viral proteins. Hemagglutinin and neuraminidase molecules cluster into a bulge in the host cell membrane. The vRNA and [[viral core]] proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the host cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).<ref>{{cite journal |vauthors=Nayak D, Hui E, Barman S | title = Assembly and budding of influenza virus | journal = Virus Res | volume = 106 | issue = 2 | pages = 147–65 |date=December 2004 | pmid = 15567494 | doi = 10.1016/j.virusres.2004.08.012| pmc = 7172797 }}</ref> As before, the viruses then adhere to the same host cell capsule through hemagglutinin; the mature viruses detach once their [[neuraminidase]] has cleaved sialic acid residues from the host cell.<ref name=Wagner/> After the release of new influenza virus, the host cell dies, and infection repeats in other host cells.
[[File:Fimmu-09-01581-g004.jpg|thumb|Transcription of mRNAs initiated by viral polymerase using [[cap snatching]]]]
Orthomyxoviridae viruses are one of two RNA viruses that replicate in the nucleus (the other being [[retroviridae]]). This is because the machinery of orthomyxo viruses cannot make their own mRNAs. They use cellular RNAs as primers for initiating the viral mRNA synthesis in a process known as [[cap snatching]].<ref>{{cite web|title=Cap Snatching|url=http://viralzone.expasy.org/all_by_protein/839.html|website=ViralZone|publisher=expasy|access-date=11 September 2014}}</ref> Once in the nucleus, the RNA Polymerase Protein PB2 finds a cellular pre-mRNA and binds to its 5′ capped end. Then RNA Polymerase PA cleaves off the cellular mRNA near the 5′ end and uses this capped fragment as a primer for transcribing the rest of the viral RNA genome in viral mRNA.<ref name=Bouvier2009>{{cite journal | vauthors = Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW | title = The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit | journal = Nature | volume = 458 | issue = 7240 | pages = 914–8 | date = April 2009 | pmid = 19194459 | doi = 10.1038/nature07745 | bibcode = 2009Natur.458..914D | s2cid = 4421958 }}</ref> This is due to the need of mRNA to have a 5′ cap in order to be recognized by the cell's [[ribosome]] for translation.

Since RNA [[Proofreading (biology)|proofreading]] enzymes are absent, the RNA-dependent RNA transcriptase makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly manufactured influenza virus will contain a mutation in its genome.<ref>{{cite journal | author = Drake J | title = Rates of spontaneous mutation among RNA viruses | journal = Proc Natl Acad Sci USA | volume = 90 | issue = 9 | pages = 4171–5 | date=May 1, 1993 | pmid = 8387212 | doi = 10.1073/pnas.90.9.4171 | pmc = 46468|bibcode = 1993PNAS...90.4171D | doi-access = free }}</ref> The separation of the genome into eight separate segments of vRNA allows mixing ([[reassortment]]) of the genes if more than one variety of influenza virus has infected the same cell ([[superinfection]]). The resulting alteration in the genome segments packaged into viral progeny confers new behavior, sometimes the ability to infect new host species or to overcome protective immunity of host populations to its old genome (in which case it is called an [[antigenic shift]]).<ref name=Hilleman/>

== Classification ==
In a [[phylogenetic]]-based [[Taxonomy (biology)|taxonomy]], [[RNA virus]]es include the subcategory [[Sense (molecular biology)|negative-sense ssRNA virus]], which includes the order ''[[Articulavirales]]'', and the family ''Orthomyxoviridae''. The family contains the following genera:<ref>{{cite web|title=Virus Taxonomy: 2024 Release|url=https://ictv.global/taxonomy|publisher=International Committee on Taxonomy of Viruses|access-date=19 March 2025}}</ref>
{{div col}}
* ''[[Alphainfluenzavirus]]''
* ''[[Betainfluenzavirus]]''
* ''[[Deltainfluenzavirus]]''
* ''[[Gammainfluenzavirus]]''
* ''[[Isavirus]]''
* ''[[Mykissvirus]]''
* ''[[Quaranjavirus]]''
* ''[[Sardinovirus]]''
* ''[[Thogotovirus]]''
{{div col end}}

== Influenza types ==
There are four genera of influenza virus, each containing only a single species, or type. Influenza A and C infect a variety of species (including humans), while influenza B almost exclusively infects humans, and influenza D infects cattle and pigs.<ref name="hay">{{cite journal|vauthors=Hay A, Gregory V, Douglas A, Lin Y|date=Dec 29, 2001|title=The evolution of human influenza viruses|journal=Philos Trans R Soc Lond B Biol Sci|volume=356|issue=1416|pages=1861–70|doi=10.1098/rstb.2001.0999|pmc=1088562|pmid=11779385}}</ref><ref>{{cite web|title=Avian Influenza (Bird Flu)|url=https://www.cdc.gov/flu/avian/|access-date=2007-09-15|publisher=Centers for Disease Control and Prevention}}</ref><ref>{{Cite journal|last1=Kumar|first1=Binod|last2=Asha|first2=Kumari|last3=Khanna|first3=Madhu|last4=Ronsard|first4=Larance|last5=Meseko|first5=Clement Adebajo|last6=Sanicas|first6=Melvin|date=April 2018|title=The emerging influenza virus threat: status and new prospects for its therapy and control|journal=Archives of Virology|volume=163|issue=4|pages=831–844|doi=10.1007/s00705-018-3708-y|issn=1432-8798|pmc=7087104|pmid=29322273}}</ref>

=== Influenza A ===
{{Main|Influenza A virus}}
[[File:InfluenzaNomenclatureDiagram.svg|thumb|right|Diagram of influenza nomenclature]]
Influenza A viruses are further classified, based on the viral surface proteins [[hemagglutinin (influenza)|hemagglutinin]] (HA or H) and [[neuraminidase]] (NA or N). 18 HA subtypes (or serotypes) and 11 NA subtypes of influenza A virus have been isolated in nature. Among these, the HA subtype 1-16 and NA subtype 1-9 are found in wild waterfowl and shorebirds and the HA subtypes 17-18 and NA subtypes 10-11 have only been isolated from bats.<ref>{{Cite journal |last=Alexander |first=Dennis J. |date=2007-07-26 |title=An overview of the epidemiology of avian influenza |journal=Vaccine |volume=25 |issue=30 |pages=5637–5644 |doi=10.1016/j.vaccine.2006.10.051 |issn=0264-410X |pmid=17126960}}</ref><ref>{{Cite journal |last1=Wu |first1=Ying |last2=Wu |first2=Yan |last3=Tefsen |first3=Boris |last4=Shi |first4=Yi |last5=Gao |first5=George F. |date=April 2014 |title=Bat-derived influenza-like viruses H17N10 and H18N11 |journal=Trends in Microbiology |volume=22 |issue=4 |pages=183–191 |doi=10.1016/j.tim.2014.01.010 |issn=0966-842X |pmc=7127364 |pmid=24582528}}</ref>

Further variation exists; thus, specific influenza strain [[Isolation (microbiology)|isolates]] are identified by the ''Influenza virus nomenclature,''<ref>{{Cite journal |date=1980 |title=A revision of the system of nomenclature for influenza viruses: a WHO Memorandum |journal=Bull World Health Organ |volume=58 |issue=4 |pages=585–591 |pmc=2395936 |pmid=6969132 |quote=This Memorandum was drafted by the signatories listed on page 590 on the occasion of a meeting held in Geneva in February 1980. }}</ref> specifying virus type, host species (if not human), geographical location where first isolated, laboratory reference, year of isolation, and HA and NA subtype.<ref>{{cite book|url=https://www.cdc.gov/vaccines/pubs/pinkbook/pink-chapters.htm|title=Epidemiology and Prevention of Vaccine-Preventable Diseases|publisher=Centers for Disease Control and Prevention|year=2007|veditors=Atkinson W, Hamborsky J, McIntyre L, Wolfe S|edition=10th|location=Washington DC}}</ref><ref>{{cite web|date=2007-06-27|title=Avian Influenza (Bird Flu): Implications for Human Disease|url=http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/biofacts/avflu_human.html|access-date=2007-09-14|publisher=Center for Infectious Disease Research & Policy, [[University of Minnesota]]}}</ref>

Examples of the nomenclature are:
# {{Tt|A/Brisbane/59/2007 (H1N1)}} - isolated from a human
# {{tt|A/swine/South Dakota/152B/2009 (H1N2)}} - isolated from a pig

The type A influenza viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. It is thought that all influenza A viruses causing outbreaks or pandemics originate from wild aquatic birds.<ref name="PMID1579108">{{Cite journal |last1=Webster |first1=R. G. |last2=Bean |first2=W. J. |last3=Gorman |first3=O. T. |last4=Chambers |first4=T. M. |last5=Kawaoka |first5=Y. |date=March 1992 |title=Evolution and ecology of influenza A viruses |journal=Microbiological Reviews |volume=56 |issue=1 |pages=152–179 |doi=10.1128/mr.56.1.152-179.1992 |issn=0146-0749 |pmid=1579108|pmc=372859 }}</ref> All influenza A virus pandemics since the 1900s were caused by [[Avian influenza]], through [[Reassortment]] with other influenza strains, either those that affect humans (seasonal flu) or those affecting other animals (see [[2009 swine flu pandemic]]).<ref>{{Cite journal |last1=Taubenberger |first1=Jeffery K. |last2=Morens |first2=David M. |date=April 2010 |title=Influenza: the once and future pandemic |journal=Public Health Reports |volume=125 |issue=Suppl 3 |pages=16–26 |doi=10.1177/00333549101250S305 |issn=0033-3549 |pmc=2862331 |pmid=20568566}}</ref> The serotypes that have been confirmed in [[humans]], ordered by the number of confirmed human deaths, are:
* [[H1N1]] caused "[[Spanish flu]]" in 1918 and "[[Swine flu]]" in 2009.<ref>{{cite journal|author2-link=Peter Palese|vauthors=Wang TT, Palese P|date=June 2009|title=Unraveling the Mystery of Swine Influenza Virus|journal=Cell|volume=137|issue=6|pages=983–85|doi=10.1016/j.cell.2009.05.032|pmid=19524497|doi-access=free}}</ref>
* [[H2N2]] caused "Asian Flu".
* [[H3N2]] caused "[[1968 flu pandemic|Hong Kong Flu]]".
* [[H5N1]], "avian" or "bird flu".<ref>{{cite journal|vauthors=Taubenberger, JK, Morens, DM|date=April 2009|title=Pandemic influenza – including a risk assessment of H5N1|journal=Rev. Sci. Tech. Off. Int. Epiz.|volume=28|issue=1|pages=187–202|doi=10.20506/rst.28.1.1879|pmc=2720801|pmid=19618626}}</ref>
* [[H7N7]] has unusual zoonotic potential.<ref>{{cite journal|vauthors=Fouchier R, Schneeberger P, Rozendaal F, Broekman J, Kemink S, Munster V, Kuiken T, Rimmelzwaan G, Schutten M, Van Doornum G, Koch G, Bosman A, Koopmans M, Osterhaus A|year=2004|title=Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome|journal=Proc Natl Acad Sci USA|volume=101|issue=5|pages=1356–61|bibcode=2004PNAS..101.1356F|doi=10.1073/pnas.0308352100|pmc=337057|pmid=14745020|doi-access=free}}</ref>
* [[H1N2]] infects pigs and humans.<ref>{{cite journal|vauthors=Malik-Peiris JS, Poon LL, Guan Y|date=July 2009|title=Emergence of a novel swine-origin influenza A virus (S-OIV) H1N1 virus in humans|journal=J Clin Virol|volume=45|issue=3|pages=169–173|doi=10.1016/j.jcv.2009.06.006|pmc=4894826|pmid=19540800}}</ref>
* [[H9N2]], [[H7N2]], [[H7N3]], [[H10N7]].

{| class="wikitable" style="text-align:center"
|+Known [[flu pandemic]]s<ref name="Hilleman" /><ref name="Potter">{{cite journal|vauthors=Potter CW|date=October 2001|title=A history of influenza|journal=Journal of Applied Microbiology|volume=91|issue=4|pages=572–9|doi=10.1046/j.1365-2672.2001.01492.x|pmid=11576290|doi-access=|s2cid=26392163 }}</ref><ref name="TenThings">{{cite web|date=14 October 2005|title=Ten things you need to know about pandemic influenza|url=https://www.who.int/csr/disease/influenza/pandemic10things/en/index.html|archive-url=https://web.archive.org/web/20090923231756/http://www.who.int/csr/disease/influenza/pandemic10things/en/index.html <!--Added by H3llBot-->|archive-date=23 September 2009|access-date=26 September 2009|publisher=World Health Organization}}</ref>
! Name of pandemic !! Date !! Deaths !![[Case fatality rate]]!! Subtype involved !![[Pandemic Severity Index]]
|-
![[1889–1890 flu pandemic]]<br />(Asiatic or Russian Flu)<ref>{{cite journal|vauthors=Valleron AJ, Cori A, Valtat S, Meurisse S, Carrat F, Boëlle PY|date=May 2010|title=Transmissibility and geographic spread of the 1889 influenza pandemic|journal=Proc. Natl. Acad. Sci. USA|volume=107|issue=19|pages=8778–81|bibcode=2010PNAS..107.8778V|doi=10.1073/pnas.1000886107|pmc=2889325|pmid=20421481|doi-access=free}}</ref>
|1889–1890 ||1 million ||0.15% || Possibly [[H3N8]] <br /> or [[H2N2]]|| {{N/A}}
|-
![[1918 flu pandemic]]<br />(Spanish flu)<ref>{{cite journal|author2-link=James Robins|vauthors=Mills CE, Robins JM, Lipsitch M|date=December 2004|title=Transmissibility of 1918 pandemic influenza|journal=Nature|volume=432|issue=7019|pages=904–06|bibcode=2004Natur.432..904M|doi=10.1038/nature03063|pmc=7095078|pmid=15602562}}</ref>
|1918–1920 ||20 to 100 million ||2%||[[H1N1]]||5
|-
![[H2N2#Asian flu|Asian Flu]]
|1957–1958 ||1 to 1.5 million ||0.13%||[[H2N2]]||2
|-
![[H3N2#Hong Kong Flu (1968–1969)|Hong Kong Flu]]
|1968–1969 ||0.75 to 1 million ||<0.1%||[[H3N2]]||2
|-
![[Influenza A virus subtype H1N1#1977 Russian flu|Russian flu]]
| 1977–1978 || {{n/a|No accurate count}} || {{N/A}} ||[[H1N1]]|| {{N/A}}
|-
![[2009 flu pandemic]]<ref>{{cite journal|author=Donaldson LJ|author2=Rutter PD|author3=Ellis BM|last4=Greaves|first4=F. E C|last5=Mytton|first5=O. T|last6=Pebody|first6=R. G|last7=Yardley|first7=I. E|display-authors=3|year=2009|title=Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study|journal=BMJ|volume=339|article-number=b5213|doi=10.1136/bmj.b5213|pmc=2791802|pmid=20007665|name-list-style=vanc}}</ref><ref name="ecdc">{{cite web|date=2010-01-18<!-- 09:00 UTC +2-->|title=ECDC Daily Update – Pandemic (H1N1) 2009 – January 18, 2010|url=http://ecdc.europa.eu/en/healthtopics/Documents/100118_Influenza_AH1N1_Situation_Report_0900hrs.pdf|url-status=dead|archive-url=https://web.archive.org/web/20100122162136/http://www.ecdc.europa.eu/en/healthtopics/Documents/100118_Influenza_AH1N1_Situation_Report_0900hrs.pdf|archive-date=January 22, 2010|access-date=2010-01-18|publisher=[[European Centre for Disease Prevention and Control]]}}</ref>
|2009–2010 || 105,700–395,600<ref>{{cite journal|vauthors=Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P, Feikin DR, Fowler KB, Gordon A, Hien NT, Horby P, Huang QS, Katz MA, Krishnan A, Lal R, Montgomery JM, Mølbak K, Pebody R, Presanis AM, Razuri H, Steens A, Tinoco YO, Wallinga J, Yu H, Vong S, Bresee J, Widdowson MA|date=September 2012|title=Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study|url=https://zenodo.org/record/1260250|journal=The Lancet. Infectious Diseases|type=Submitted manuscript|volume=12|issue=9|pages=687–95|doi=10.1016/S1473-3099(12)70121-4|pmid=22738893 |via=Zenodo |url-status=live |archive-url= https://web.archive.org/web/20240409153139/https://zenodo.org/records/1260250/files/article.pdf?download=1 |archive-date= Apr 9, 2024 }}</ref>||0.03%||[[H1N1]]||N/A
|}

=== Influenza B ===
{{Main|Influenza B virus}}
[[File:Vetsci-05-00071-g001.webp|thumb|Host range of influenza viruses]]
Influenza B virus is almost exclusively a human pathogen, and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the [[Pinniped|seal]].<ref>{{cite journal|vauthors=Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA|date=May 2000|title=Influenza B virus in seals|journal=Science|volume=288|issue=5468|pages=1051–3|bibcode=2000Sci...288.1051O|doi=10.1126/science.288.5468.1051|pmid=10807575}}</ref> This type of influenza mutates at a rate 2–3 times lower than type A<ref>{{cite journal|vauthors=Nobusawa E, Sato K|date=April 2006|title=Comparison of the mutation rates of human influenza A and B viruses|journal=Journal of Virology|volume=80|issue=7|pages=3675–8|doi=10.1128/JVI.80.7.3675-3678.2006|pmc=1440390|pmid=16537638}}</ref> and consequently is less genetically diverse, with only one influenza B serotype.<ref name="hay" /> As a result of this lack of [[antigen]]ic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.<ref name="PMID1579108" /> This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species [[antigenic shift]]), ensures that pandemics of influenza B do not occur.<ref name="Zambon">{{cite journal|vauthors=Zambon MC|date=November 1999|title=Epidemiology and pathogenesis of influenza|journal=The Journal of Antimicrobial Chemotherapy|volume=44 Suppl B|issue=Suppl B|pages=3–9|doi=10.1093/jac/44.suppl_2.3|pmid=10877456|s2cid=15968981|doi-access=free}}</ref>

=== Influenza C ===
{{Main|Influenza C virus}}

The influenza C virus infects [[human]]s and [[pig]]s, and can cause severe illness and local [[epidemic]]s.<ref>{{cite journal|vauthors=Matsuzaki Y, Sugawara K, Mizuta K, Tsuchiya E, Muraki Y, Hongo S, Suzuki H, Nakamura K|year=2002|title=Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998|journal=J Clin Microbiol|volume=40|issue=2|pages=422–29|doi=10.1128/JCM.40.2.422-429.2002|pmc=153379|pmid=11825952}}</ref> However, influenza C is less common than the other types and usually causes mild disease in children.<ref>{{cite journal|vauthors=Matsuzaki Y, Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H|date=May 1, 2006|title=Clinical features of influenza C virus infection in children|journal=J Infect Dis|volume=193|issue=9|pages=1229–35|doi=10.1086/502973|pmid=16586359|doi-access=free}}</ref><ref>{{cite journal|vauthors=Katagiri S, Ohizumi A, Homma M|date=July 1983|title=An outbreak of type C influenza in a children's home|journal=J Infect Dis|volume=148|issue=1|pages=51–56|doi=10.1093/infdis/148.1.51|pmid=6309999}}</ref>

=== Influenza D ===
{{Main|Influenza D virus}}

This is a genus that was classified in 2016, the members of which were first isolated in 2011.<ref name="Hause2013">{{cite journal|vauthors=Hause BM, Ducatez M, Collin EA, Ran Z, Liu R, Sheng Z, Armien A, Kaplan B, Chakravarty S, Hoppe AD, Webby RJ, Simonson RR, Li F|date=February 2013|title=Isolation of a novel swine influenza virus from Oklahoma in 2011 which is distantly related to human influenza C viruses|journal=PLOS Pathogens|volume=9|issue=2|article-number=e1003176|doi=10.1371/journal.ppat.1003176|pmc=3567177|pmid=23408893 |doi-access=free }}</ref> This genus appears to be most closely related to Influenza C, from which it diverged several hundred years ago.<ref name="Sheng2014">{{cite journal|vauthors=Sheng Z, Ran Z, Wang D, Hoppe AD, Simonson R, Chakravarty S, Hause BM, Li F|date=February 2014|title=Genomic and evolutionary characterization of a novel influenza-C-like virus from swine|journal=Archives of Virology|volume=159|issue=2|pages=249–55|doi=10.1007/s00705-013-1815-3|pmc=5714291|pmid=23942954}}</ref> There are at least two extant strains of this genus.<ref name="Collin2015">{{cite journal|vauthors=Collin EA, Sheng Z, Lang Y, Ma W, Hause BM, Li F|date=January 2015|title=Cocirculation of two distinct genetic and antigenic lineages of proposed influenza D virus in cattle|journal=Journal of Virology|volume=89|issue=2|pages=1036–42|doi=10.1128/JVI.02718-14|pmc=4300623|pmid=25355894}}</ref> The main hosts appear to be cattle, but the virus has been known to infect pigs as well.

== Epidemiology ==

===Evolution and history===
[[File:Genetic Relationships Among Human and Swine Influenza Viruses, 1918-2009 (7704014350).jpg|thumb|Genetic evolution of human and swine influenza viruses, 1918–2009]]
{{Also|Timeline of influenza}}
The predominant natural reservoir of influenza viruses is thought to be wild waterfowl.<ref>{{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/ }}</ref> A 2023 involving total RNA sequencing and transcriptome mining found that Influenzaviruses and the broader ''[[Articulavirales]]'' order likely had an aquatic origin, with fish being some of the earliest hosts, and the earliest viruses in the order evolving from [[Crustaceans]] over 600 million years ago.<ref name="aquatic origins">{{cite journal|url=https://www.biorxiv.org/content/10.1101/2023.02.15.528772v1.full|title=Evidence for an aquatic origin of influenza virus and the order Articulavirales|journal=Preprint|volume=|issue=|pages=|author1=Mary E. Petrone|author2=Rhys Parry|author3=Jonathon C. O. Mifsud|author4=Kate Van Brussel|author5=Ian Vorhees|author6=Zoe T. Richards|author7=Edward C. Holmes|publisher=[[BioRxiv]]|date=16 February 2023|access-date=27 November 2025|doi=10.1101/2023.02.15.528772|doi-access=free|hdl=|hdl-access=}}</ref> 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.<ref name="origin">{{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 }}</ref>

Outbreaks of influenza-like disease can be found throughout recorded history. The first probable record is by [[Hippocrates]] in 412 BCE.<ref name="Flu-History">{{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 }}</ref> The historian Fujikawa listed 46 epidemics of flu-like illness in Japan between 862 and 1868.<ref>{{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 }}</ref> In Europe and the Americas, a number of epidemics were recorded through the [[Middle Ages]] and up to the end of the 19th century.<ref name="Flu-History" />[[File:Viruses-10-00497-g004.png|thumb|Timeline of flu pandemics and epidemics caused by influenza A virus]]In 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.<ref>{{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)}}</ref> The next pandemic took place in 1957, the "[[1957–1958 influenza pandemic|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.<ref name="Knobler-2005">{{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 }}</ref> 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.<ref name="Knobler-2005" />

In the 21st century, a strain of H1N1 flu (since titled "[[Pandemic H1N1/09 virus|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 "[[2009 swine flu pandemic|swine flu]]".<ref>{{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)}}</ref>

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.<ref name="FluGlobal-Avian">{{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}}</ref> As of June 2024, two particularly virulent IAV strains - [[Influenza A virus subtype H5N1|H5N1]] and [[Influenza A virus subtype H7N9|H7N9]] – are predominant in wild bird populations. These frequently cause outbreaks in domestic poultry, with occasional [[Spillover infection|spillover]] infections in humans who are in close contact with poultry.<ref>{{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 }}</ref><ref>{{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 }}</ref>

=== Pandemic potential ===
Influenza viruses have a relatively high mutation rate that is characteristic of [[RNA virus]]es.<ref name="SanjuanNebot20102">{{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 }}</ref> 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.<ref name="Kou22">{{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 }}</ref><ref name="WHOinfluenza22">{{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''</ref> 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 [[Zoonosis|zoonotic]] event.<ref name=":B42">{{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) }}</ref> It is thought that all influenza A viruses causing outbreaks or [[pandemic]]s among humans since the 1900s originated from strains circulating in wild aquatic birds through reassortment with other influenza strains.<ref name=":B02">{{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 }}</ref><ref name="PMID1579108" /> It is possible (though not certain) that pigs may act as an intermediate host for reassortment.<ref>{{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 }}</ref>

=== Surveillance ===
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.<ref name="Fange">{{cite book |vauthors=Lee K, Fang J |url=https://books.google.com/books?id=9zCEmpopjG0C&dq=%22WHO%22+%22GISRS+is+a%22&pg=PA163 |title=Historical Dictionary of the World Health Organization |publisher=Rowman & Littlefield |year=2013 |isbn=9780810878587}}</ref> Several millions of specimens are tested by the GISRS network annually through a network of laboratories in 127 countries.<ref name=":B03">{{Cite web |date=19 September 2022 |title=70 years of GISRS – the Global Influenza Surveillance & Response System |url=https://www.who.int/news-room/feature-stories/detail/seventy-years-of-gisrs---the-global-influenza-surveillance---response-system |access-date=13 June 2024 |publisher=World Health Organization }}</ref> As well as human viruses, GISRS also monitors avian, swine, and other potentially [[Zoonosis|zoonotic]] influenza viruses.

=== Seasonal flu ===
{{Main|Flu season}}
[[File:CDC-influenza-pneumonia-deaths-2015-01-10.gif|thumb|Seasonal variation in deaths due to influenza or pneumonia in 122 U.S. cities, as a proportion of all causes<ref name="weekly">[https://www.cdc.gov/flu/weekly/ CDC U.S. influenza season summary with weekly updates] See section 'Pneumonia and Influenza (P&I) Mortality Surveillance' ''www.cdc.gov'', accessed 30 September 2020</ref>]]

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 virus|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.<ref>{{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 | article-number = e0153003 | date = 27 April 2016 | pmid = 27119988 | pmc = 4847850 | doi = 10.1371/journal.pone.0153003 | doi-access = free | bibcode = 2016PLoSO..1153003H }}</ref> Annually, about 3 to 5&nbsp;million cases of severe illness and 290,000 to 650,000 deaths from seasonal flu occur worldwide.<ref name="WHO-Seasonal-2024">{{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 }}</ref>

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.<ref name="Harvard-2014">{{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. }}</ref>
* 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.<ref name="Harvard-2014" />
* The influenza virus may survive better in colder, drier climates, and therefore be able to infect more people.<ref name="Harvard-2014" />
* Cold air reduces the ability of the nasal membranes to resist infection.<ref>{{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 }}</ref>

=== Zoonotic infections ===
A [[zoonosis]] is 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]].<ref name="mw">{{cite Merriam-Webster|zoonosis|access-date=29 March 2019}}</ref><ref name="WHO-Zoonoses-2020">{{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 }}</ref> 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.<ref name="ecdc-annual-2022">{{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 }}</ref> A wide range of Influenza A virus subtypes have been found to cause zoonotic disease.<ref name="ecdc-annual-2022" /><ref name="FAO-2020">{{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 }}</ref>

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]].<ref name="WHO-Zoonoses-2020" />

As of June 2024, there is concern about two subtypes of avian influenza which are circulating in wild bird populations worldwide, [[Influenza A virus subtype H5N1|H5N1]] and [[Influenza A virus subtype H7N9|H7N9]]. Both of these have potential to devastate poultry stocks, and both have jumped to humans with relatively high [[case fatality rate]]s.<ref name="FAO-2020" /> H5N1 in particular has infected a [[List of mammals that can get H5N1|wide range of mammals]] and may be adapting to mammalian hosts.<ref>{{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 }}</ref>

== Signs and symptoms ==
{{Main|Influenza}}

=== Humans ===
[[File:Symptoms_of_influenza.svg|thumb|Symptoms of influenza,<ref>{{cite web |date=10 July 2019 |title=Flu Symptoms & Diagnosis |url=https://www.cdc.gov/flu/symptoms/index.html |url-status=live |archive-url=https://web.archive.org/web/20191227211854/https://www.cdc.gov/flu/symptoms/index.html |archive-date=27 December 2019 |access-date=24 January 2020 |website=U.S. [[Centers for Disease Control and Prevention]] (CDC)}}</ref><ref>{{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]]}}</ref> with fever and cough the most common symptoms<ref name="pmid15728170">{{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 }}</ref>]]

The symptoms of seasonal flu are similar to those of a [[Common cold|cold]], although usually more severe and less likely to include a [[runny nose]].<ref>{{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) }}</ref> 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.<ref>{{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 }}</ref>

Humans can rarely become infected with strains of [[Avian influenza|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.<ref name="GOV.UK-2021">{{Cite web |date=18 November 2021 |title=Avian influenza: guidance, data and analysis |url=https://www.gov.uk/government/collections/avian-influenza-guidance-data-and-analysis |access-date=9 May 2024 |website=GOV.UK }}</ref><ref name="ECDC-Swine-2017">{{Cite web |date=20 September 2017 |title=Swine influenza in humans |url=https://www.ecdc.europa.eu/en/swine-influenza-humans |access-date=17 June 2024 |publisher=European Centre for Disease Prevention and Control (ECDC) }}</ref>

=== Other animals ===

==== Birds ====
{{Main|Avian influenza}}

Some species of wild [[Water bird|aquatic birds]] act as natural [[asymptomatic carrier]]s of a large variety of influenza A viruses, which they can spread over large distances in their annual migration.<ref>{{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 }}</ref> 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.<ref>{{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)}}</ref>

===== Highly pathogenic avian influenza =====
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.<ref name=":AA6">{{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 = }}</ref> Classification of a virus strain as either a low or high pathogenic strain is based on the severity of symptoms in domestic [[chicken]]s 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.<ref name="CDC-2022">{{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) }}</ref>

Since 2006, the [[World Organisation for Animal Health|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.<ref>{{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}}</ref>

==== Pigs ====
{{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;<ref>{{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 }}</ref> it is spread either through close contact between animals or by the movement of contaminated equipment between farms.<ref>{{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) }}</ref> Humans who are in close contact with pigs can sometimes become infected.<ref>{{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 }}</ref>

==== Horses ====
{{Main|Equine influenza}}
Equine influenza can affect horses, donkeys, and mules;<ref>{{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 }}</ref> it has a very high rate of transmission among horses, and a relatively short [[Incubation period|incubation time]] of one to three days.<ref name="Merck-Vet">{{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}}</ref> Clinical signs of equine influenza include fever, nasal discharge, have a dry, hacking cough, depression, loss of appetite and weakness.<ref name="Merck-Vet" /> EI is caused by two subtypes of influenza A viruses: H7N7 and H3N8, which have evolved from avian influenza A viruses.<ref>{{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) }}</ref>

==== Dogs ====
{{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.<ref name="CDC-Canine-2023" /> There are two different influenza A dog flu viruses: one is an H3N8 virus and the other is an H3N2 virus.<ref name="CDC-Canine-2023">{{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) }}</ref> 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.<ref name="CDC-Canine-2023" /> 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.<ref>{{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 | article-number = a038562 | date = January 2021 | pmid = 31871238 | pmc = 7778219 | doi = 10.1101/cshperspect.a038562 }}</ref>

==== Bats ====
{{Main|Bat influenza}}
The first bat flu virus, IAV(H17N10), was first discovered in 2009 in [[little yellow-shouldered bat]]s (''Sturnira lilium'') in [[Guatemala]].<ref name="swwa">{{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 |date=10 July 2024 }}</ref> In 2012 a second bat influenza A virus IAV(H18N11) was discovered in [[flat-faced fruit-eating bat]]s (''Artibeus planirostris'') from [[Peru]].<ref>{{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}}</ref><ref>{{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}}</ref><ref name="Schwemmle">{{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 | article-number = e1008384 | date = April 2020 | pmid = 32298389 | pmc = 7161946 | doi = 10.1371/journal.ppat.1008384 | doi-access = free }}</ref> Bat influenza viruses have been found to be poorly adapted to non-bat species.<ref>{{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 }}</ref>

== Viability and disinfection ==
Mammalian influenza viruses tend to be labile, but they can survive several hours in a host's mucus.<ref name="cfsph.iastate.edu">{{cite web | first = Anna Rovid | last = Spickler | name-list-style = vanc | title  = Influenza | url = http://www.cfsph.iastate.edu/Factsheets/pdfs/influenza.pdf | page = 7 | date = February 2016 | work = The Center for Food Security and Public Health | publisher = Iowa State University }}</ref> Avian influenza virus can survive for 100 days in distilled water at room temperature and for 200 days at {{convert|17|°C}}. The avian virus is inactivated more quickly in manure but can survive for up to two weeks in feces on cages. Avian influenza viruses can survive indefinitely when frozen.<ref name="cfsph.iastate.edu" /> Influenza viruses are susceptible to bleach, 70% ethanol, aldehydes, oxidizing agents and quaternary ammonium compounds. They are inactivated by heat at {{convert|133|°F}} for minimum of 60 minutes, as well as by low pH <2.<ref name="cfsph.iastate.edu" />

== Vaccination and prophylaxis ==
{{Main|Influenza vaccine}}
[[File:Viruses-10-00497-g007.png|thumb|Targets of anti-influenza agents that are licensed or under investigation]]
Vaccines and drugs are available for the prophylaxis and treatment of influenza virus infections. Vaccines are composed of either inactivated or live attenuated virions of the H1N1 and H3N2 human influenza A viruses, as well as those of influenza B viruses. Because the antigenicities of the wild viruses evolve, vaccines are reformulated annually by updating the seed strains.<ref name="Hood">{{Cite journal |last=Hood |first=Ernie |title=Flu Vaccine Production Gets a Shot in the Arm |journal=Environmental Health Perspectives |date=2006 |volume=114 |issue=2 |pages=A108–A111 |doi=10.1289/ehp.114-a108 |pmc=1367863 |pmid=16451835 }}</ref>

More specifically, flu vaccines are made using the reassortment method, and this has been used for over 50 years. In this method, scientists inject eggs with both one noninfectious flu strain and also one infectious strain. The inert strain must be one that multiples very well in chicken eggs. Scientists pick an infectious strain that carries the desired HA and N receptors that the final product should prevent from infection. They choose these strains by picking the surface HA and NA versions circulating the most in the public, and the ones thought most likely to be prevalent in the upcoming flu season. The two strains—pathogenic and non pathogenic—then multiply and exchange DNA until an inert strain carries eight copies of the infectious strain's two glycoprotein targets. Finally, of the newly created viruses, scientists pick six versions that multiplied the best in chicken eggs which also carry the necessary HA and NA genes. Ultimately, millions of eggs are injected with those noninfectious strains—which carry the desired proteins—so that the genes can be harvested and used for the vaccine product.<ref name="Hood" />

Another method of making the vaccine is by splicing genes from infectious strains and then creating copies in a lab, without the need for the tedious process of chicken egg culture. This method relies on using virus plasmids to excerpt the target genes.<ref name="Hood" />

When the antigenicities of the seed strains and wild viruses do not match, vaccines fail to protect the vaccines.<ref name="Hood" />

Drugs available for the treatment of influenza include [[Amantadine]] and [[Rimantadine]], which inhibit the uncoating of virions by interfering with [[M2 proton channel]], and [[Oseltamivir]] (marketed under the brand name [[Tamiflu]]), [[Zanamivir]], and [[Peramivir]], which inhibit the release of virions from infected cells by interfering with [[Viral neuraminidase|NA]]. However, escape mutants are often generated for the former drug and less frequently for the latter drug.<ref>{{cite journal | vauthors = Suzuki Y | title = Natural selection on the influenza virus genome | journal = Molecular Biology and Evolution | volume = 23 | issue = 10 | pages = 1902–11 | date = October 2006 | pmid = 16818477 | doi = 10.1093/molbev/msl050 | doi-access = free |publisher=Oxford Academic |url=https://academic.oup.com/mbe/article/23/10/1902/1096939 |url-status=live |archive-url=https://web.archive.org/web/20220121124029/https://academic.oup.com/mbe/article/23/10/1902/1096939 |archive-date= Jan 21, 2022 }}</ref>

== See also ==
{{Portal|Viruses}}
* [[Influenza-like illness]]
* [[Coronavirus]]
* [[Rhinovirus]]

== References ==
{{Reflist|32em}}

== Further reading ==
{{Refbegin}}
* {{cite book |author=Hoyle, L. |title=The Influenza Viruses |series=Virology Monographs |volume=4 |publisher=Springer-Verlag |year=1969 |isbn=978-3-211-80892-4 |url=https://books.google.com/books?id=aCowRwAACAAJ |oclc=4053391 |issn=0083-6591}}
{{Refend}}

== External links ==
{{Wikispecies}}
{{Refbegin}}
* [http://ec.europa.eu/health-eu/health_problems/avian_influenza/index_en.htm Health-EU Portal]: EU work to prepare a global response to influenza.
* [http://www.fludb.org Influenza Research Database]: Database of influenza genomic sequences and related information.
* [http://ec.europa.eu/health/ph_threats/com/Influenza/h1n1_en.htm European Commission—Public Health]: EU coordination on Pandemic (H1N1) 2009
* [http://www.pdbe.org/emsearch/influenza 3D Influenza-virus-related structures from the EM Data Bank (EMDB)]
* [http://viralzone.expasy.org/all_by_species/223.html Viralzone: Orthomyxoviridae]
{{Refend}}

{{Baltimore classification}}
{{Common cold}}
{{Influenza}}
{{Taxonbar|from=Q287246}}
{{Authority control}}

[[Category:Orthomyxoviridae| ]]
[[Category:Virus families]]