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| {{Influenza}} | | {{Influenza}} |
| {{CMG}} | | {{CMG}} |
| | ==Overview== |
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| ==Classification== | | ==Classification== |
| [[Image:3D influenza virus.png|thumb|400px|left|Structure of the influenza [[wikt:virion|virion]]. The [[hemagglutinin]] (HA) and [[neuraminidase]] (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the [[genome]] are shown as red coils inside the particle and bound to Ribonuclear Proteins (RNPs).]]
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| [[Image:Infnomenclature.svg|thumb|350px|right|Diagram of influenza virus [[International Committee on Taxonomy of Viruses|nomenclature]] (for a [[Fujian flu]] virus)]]
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| The influenza virus is an [[RNA virus]] of the family [[Orthomyxoviridae]], which comprises the influenzaviruses, [[Isavirus]], and [[Thogotovirus]].<ref name=Kawaoka>{{cite book | author = Kawaoka Y (editor). | title = Influenza Virology: Current Topics | publisher = Caister Academic Press | year = 2006 | url=http://www.horizonpress.com/flu | isbn = 978-1-904455-06-6}}</ref> There are three types of influenza virus: [[Influenzavirus A]], [[Influenzavirus B]], and [[Influenzavirus C]]. Influenza A and C infect multiple species, while influenza B almost exclusively infects humans.<ref name=hay>{{cite journal | last = Hay | first = A | coauthors = Gregory V, Douglas A, Lin Y | title = The evolution of human influenza viruses | journal = Philos Trans R Soc Lond B Biol Sci | volume = 356 | issue = 1416 | pages = 1861–70 | year = 2001 | month=Dec 29 | id = PMID 11779385}}</ref>
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| Wild aquatic birds are the natural hosts for a large variety of influenza A viruses. Occasionally viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza [[pandemic]]s.<ref name=sobrino6>{{cite book |chapterurl=http://www.horizonpress.com/avir|author=Klenk et al|year=2008|chapter=Avian Influenza: Molecular Mechanisms of Pathogenesis and Host Range|title=Animal Viruses: Molecular Biology|publisher=Caister Academic Press|isbn = 978-1-904455-22-6}}</ref>
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| The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The Influenza A virus can be subdivided into different [[serovar|serotype]]s based on the [[antibody]] response to these viruses.<ref name=hay/> The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:
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| *[[H1N1]] caused "[[Spanish Flu]]."
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| *[[H2N2]] caused "Asian Flu."
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| *[[H3N2]] caused "Hong Kong Flu."
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| *[[H5N1]] is a [[pandemic]] threat in 2007–8 flu season.
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| *[[H7N7]] has unusual [[zoonotic]] potential.<ref>{{cite journal | last = Fouchier | first = R | coauthors = 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 | title = Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. | url= http://www.pnas.org/cgi/content/full/101/5/1356 | journal = Proc Natl Acad Sci U S A | volume = 101 | issue = 5 | pages = 1356–61 | year = 2004 | id = PMID 14745020}}</ref>
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| *[[H1N2]] is endemic in humans and pigs.
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| *[[H9N2]], [[H7N2]], [[H7N3]], [[H10N7]].
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| 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 | last = Osterhaus | first = A | coauthors = Rimmelzwaan G, Martina B, Bestebroer T, Fouchier R | title = Influenza B virus in seals. | journal = Science | volume = 288 | issue = 5468 | pages = 1051–3 | year = 2000 | id = PMID 10807575}}</ref> This type of influenza mutates at a rate 2–3 times lower than type A<ref>{{cite journal | last = Nobusawa | first = E | coauthors = Sato K | title = Comparison of the mutation rates of human influenza A and B viruses | journal = J Virol | volume = 80 | issue = 7 | pages = 3675–8 | year = 2006 | month=Apr | id = 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 (medical)|immunity]] to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.<ref name=webster>{{cite journal | first = Webster | last = R | coauthors = Bean W, Gorman O, Chambers T, Kawaoka Y | title = Evolution and ecology of influenza A viruses. | url= http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1579108 |journal = Microbiol Rev | volume = 56 | issue = 1 | pages = 152–79 | year = 1992 | id = PMID 1579108}}</ref> 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 | last = Zambon | first = M | title = Epidemiology and pathogenesis of influenza. | journal = J Antimicrob Chemother | volume = 44 Suppl B | issue = | pages = 3–9 | year = 1999 | month=Nov | id = PMID 10877456 | url=http://jac.oxfordjournals.org/cgi/reprint/44/suppl_2/3}}</ref>
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| The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.<ref name = "Matsuzaki">{{cite journal | last = Matsuzaki | first = Y | coauthors = Sugawara K, Mizuta K, Tsuchiya E, Muraki Y, Hongo S, Suzuki H, Nakamura K | title = Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998 | url= http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11825952 | journal = J Clin Microbiol | volume = 40 | issue = 2 | pages = 422–9 | year = 2002 | id = PMID 11825952}}</ref> However, influenza C is less common than the other types and usually seems to cause mild disease in children.<ref>{{cite journal | last = Matsuzaki | first = Y | coauthors = Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H | title = Clinical features of influenza C virus infection in children. | journal = J Infect Dis | volume = 193 | issue = 9 | pages = 1229–35 | year = 2006 | month=May 1 | id = PMID 16586359}}</ref><ref name = "Katagiri">{{cite journal | last = Katagiri | first = S | coauthors = Ohizumi A, Homma M | title = An outbreak of type C influenza in a children's home. | journal = J Infect Dis | volume = 148 | issue = 1 | pages = 51–6 | year = 1983 | month=Jul | id = PMID 6309999}}</ref>
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| ===Structure and properties===
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| The following applies for [[Influenzavirus A|Influenza A]] viruses, although other strains are very similar in structure:<ref>International Committee on Taxonomy of Viruses descriptions of: [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/46000000.htm Orthomyxoviridae], [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/46040000.htm Influenzavirus B] and [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.046.0.02.htm Influenzavirus C]</ref>
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| The influenza A virus particle or ''virion'' is 80–120 nm in diameter and usually roughly spherical, although filamentous forms can occur.<ref>{{cite web |author= International Committee on Taxonomy of Viruses |title=The Universal Virus Database, version 4: Influenza A |url=http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/00.046.0.01.htm}}</ref> Unusually for a virus, the influenza A [[genome]] is not a single piece of [[nucleic acid]]; instead, it contains eight pieces of segmented [[negative-sense]] [[RNA]] (13.5 kilobases total), which encode 10 [[protein]]s (HA (hemagglutinin), NA (neuraminidase), NP (nucleoprotein), M1, M2, NS1, PA, PB1, PB1-F2, PB2).<ref name=Ghedin>{{cite journal | last = Ghedin | first = E | coauthors = Sengamalay N, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro D, Sitz J, Koo H, Bolotov P, Dernovoy D, Tatusova T, Bao Y, St George K, Taylor J, Lipman D, Fraser C, Taubenberger J, Salzberg S | title = Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. | journal = Nature | volume = 437 | issue = 7062 | pages = 1162–6 | year = 2005 | month=Oct 20 | id = PMID 16208317}}</ref> The best-characterised of these viral proteins are [[hemagglutinin]] and [[neuraminidase]], two large [[glycoprotein]]s found on the outside of the viral particles. Neuraminidase is an [[enzyme]] involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. By contrast, 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 | last = Suzuki | first = Y | title = Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses. | url= http://www.jstage.jst.go.jp/article/bpb/28/3/399/_pdf | journal = Biol Pharm Bull | volume = 28 | issue = 3 | pages = 399–408 | year = 2005 | id = PMID 15744059}}</ref> The hemagglutinin (HA or H) and neuraminidase (NA or N) proteins are targets for [[antiviral drugs]].<ref>{{cite journal | last = Wilson | first = J | coauthors = von Itzstein M | title = Recent strategies in the search for new anti-influenza therapies | journal = Curr Drug Targets | volume = 4 | issue = 5 | pages = 389–408 | year = 2003 | month=Jul | id = PMID 12816348}}</ref> These proteins are also recognised by [[antibody|antibodies]], i.e. they are [[antigen]]s. The responses of antibodies to these proteins are used to classify the different [[serovar|serotype]]s of influenza A viruses, hence the ''H'' and ''N'' in ''H5N1''.
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| ===Infection and replication===
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| [[Image:Virus Replication.svg|thumb|400px|left|Host cell invasion and replication by the influenza virus. The steps in this process are discussed in the text.]]
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| Influenza viruses bind through [[hemagglutinin]] onto [[sialic acid]] sugars on the surfaces of [[epithelium|epithelial cells]]; typically in the nose, throat and [[lung]]s of mammals and [[intestine]]s of birds (Stage 1 in infection figure).<ref name=Wagner>{{cite journal | last = Wagner | first = R | coauthors = 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 | year = 2002 | month=May–Jun| id = PMID 11987141}}</ref> The cell imports the virus by [[endocytosis]]. In the acidic [[endosome]], part of the haemagglutinin protein fuses the viral envelope with the vacuole's membrane, releasing the viral RNA (vRNA) molecules, accessory proteins and [[RNA replicase|RNA-dependent RNA transcriptase]] into the [[cytoplasm]] (Stage 2).<ref>{{cite journal | last = Lakadamyali | first = M | coauthors = Rust M, Babcock H, Zhuang X | title = Visualizing infection of individual influenza viruses. | journal = Proc Natl Acad Sci U S A | volume = 100 | issue = 16 | pages = 9280–5 | year = 2003 | month=Aug 5 | id = PMID 12883000}}</ref> These proteins and vRNA form a complex that is transported into the [[cell nucleus]], where the RNA-dependent RNA transcriptase begins transcribing complementary positive-sense vRNA (Steps 3a and b).<ref>{{cite journal | last = Cros | first = J | coauthors = 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 | year = 2003 | month=Sep | id = PMID 12921991}}</ref> The vRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly-synthesised viral proteins are either secreted through the [[Golgi apparatus]] onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to 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 the released [[nucleotide]]s for vRNA synthesis and also inhibiting [[translation (biology)|translation]] of host-cell mRNAs.<ref>{{cite journal | last = Kash | first = J | coauthors = 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 | year = 2006 | month=Jul | id = PMID 16630668}}</ref>
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| Negative-sense vRNAs that form the [[genome]]s of future viruses, RNA-dependent RNA transcriptase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the 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 cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).<ref>{{cite journal | last = Nayak | first = D | coauthors = Hui E, Barman S | title = Assembly and budding of influenza virus. | journal = Virus Res | volume = 106 | issue = 2 | pages = 147–65 | year = 2004 | month =Dec | id = PMID 15567494}}</ref> As before, the viruses adhere to the cell 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.
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| Because of the absence of RNA proofreading enzymes, 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 is a mutant.<ref>{{cite journal | last = Drake | first = J | title = Rates of spontaneous mutation among RNA viruses. | journal = Proc Natl Acad Sci USA | volume = 90 | issue = 9 | pages = 4171–5 | year = 1993 | month=May 1 | id = PMID 8387212}}</ref> The separation of the genome into eight separate segments of vRNA allows mixing or ''reassortment'' of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces [[antigenic shift]]s and allow the virus to infect new host species and quickly overcome protective immunity. This is important in the emergence of pandemics, as discussed in [[#Epidemiology|Epidemiology]].
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| ==References== | | ==References== |
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| [[Category:Infectious disease]] | | [[Category:Infectious disease]] |
| [[Category:Primary care]] | | [[Category:Primary care]] |
| [[Category:Needs overview]]
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| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |