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presented by Jan Haas Institute for Immunology Influenzaviruses: Orthomyxoviridae 16 Haemagglutinin 9 Neuraminidase - types 3 Polymerase Subunits Nucleoprotein Nuclear Export Protein (NEP) Matrix Protein (M1) Ion Channel Protein (M2) Interferon Antagonist (NS1) PB1-F2 Protein The viral life cycle o(-) RNA virus oenveloped oInfluenza A responsible for pandemic outbreaks ospread via aerosols and droplets Historical overview Genetic Relationships among Human and ‘Russian’ influenza (H1N1, 1977) Relevant Swine Influenza Viruses, 1918– ‘Spanish’ influenza (H1N1, 1918-1919) otheunusual: re-emerging H1N1 virus did not replace 2009. the o mortality pattern young adults H3N2 viruses circulating at systemic the time Yellow arrows reflect exportation of one or more orestricted to the respiratory tract, lack of ‘Asian’ influenza (H2N2, 1957-1958) oboth subtypes are co-circulating in humans thisthe avian influenza A virus gene genes to from infection owasday caused by a human/avian reassortant that ‘H5N1’ influenza (1997-2003) pool. The dashed red arrow indicates a period omost patients died of bacterial pneumonia, some introduced avian virus H2 HA and N2 NA genes oHong Kong: highly pathogenic avian virus between viruses of these subtypes without circulation. Solid red arrows indicate the as well of viral oreassortment pneumonia into human populations osix marked firsttoviruses reported of humans withvirus resulted in fatalities, the emergence ofthe H1N2 in fatal infections evolutionary paths of human influenza ‘Hongkong’ influenza (H3N2, 1968-1970) oaberrant innate immune responses contributing avian influenza populations in viruses 2001subtype werelineages; oviruses of the H2N2 replacedsolid by blue arrows, of swine influenza its virulence human ofurthermore, the Asian influenza virus also oafter a period of local and sporadic outbreaks, a new outbreak arrow, of a oH1N2 viruses have sincereassortant disappeared. viruspossessed lineages; and the blue-to-red another human/avian that possessed started a PB1 gene of avian virus origin swine-origin human influenza virus. All influenza 2003 an H3 HAingene of avian virus origin osustained human-to-human infection hascontain not occurred A viruses eight genes that encode the oH5N1the viruses are characterized by avirus highproteins mortality ratefrom but top to bottom following (shown oagain, PB1 gene of the pandemic was inefficient among derived fromspread an avian virushumans within each virus): polymerase PB2, polymerase PB1, efficiently polymeraseamong PA, hemagglutinin in contrast, S-OIVs seem to spread humans but (HA), nuclear protein (NP), neuraminidase (NA), ‘S-OIV H1N1’ influenza have caused a limited number (2009) of fatal infections proteins (M), and oS-OIVs probably resulted frommatrix the reassortment of nonstructural recent Northproteins (NS). The genes theavian/human/swine 1918 human and swine American H3N2 and H1N2 swine viruses (thatofis, and the 1979 H1N1 influenza A viruses ‘triple’ reassortant viruses) with H1N1 Eurasian avian-like swine viruses recentlyAmerican descended fromvirus avian oS-OIVs possess: PB2 and PAwere genesallof North avian influenza genes,HAand some been origin, a PB1 gene of human H3N2 virusAorigin, (H1), NP, have and NS “donated” to NA the pandemic H1N1of strain. genes of classical swine virus origin, and (N1) andhuman M genes Eurasian avian-like swine virus origin (hence their original description as ‘quadruple’ reassortants) Genesis of swine-origin H1N1 influenza viruses ‘mixing vessel’ Electron microscopic picture: H1N1 Role of HA in viral pathogenicity Receptor distribution on host cells: ohuman influenza preferentially bind to sialic acid that is linked to galactose by an a2,6linkage (SAa2,6Gal) othis preference is matched by SAa2,6Gal on epithelial cells in the human trachea oin contrast, avian influenza viruses preferentially recognize SAa2,3Gal that is matched by SAa2,3Gal on epithelial cells in the intestinal tract of waterfowl (the main replication site of avian influenza viruses) osurprisingly H5N1 binds preferentially to SAa2,3Gal ostudies showed avian-type receptors (SAa2,3Gal) on human epithelial cells that line the respiratory bronchiole and the alveolar walls, but human-type receptors (SAa2,6Gal) on human epithelial cells in nasal mucosa, paranasal sinuses, pharynx, trachea and bronchi HA receptor specificity: amino acid residues in the HA receptor binding pocket determine binding to human/avian type receptors HA cleavage: HA cleavability determined by the amino acid sequence at the cleavage site oLow pathogenic viruses possess a Arg residue at the cleavage site ohighly pathogenic H5 and H7 viruses possess several basic amino acids at the HA cleavage site pathogenicity correlates with acquisition of multibasic HA cleavage sites Role of PB2, NS1 and PB1-F2 in pathogeniciy and host specificity PB2: belongs to the viral replication complex PB1-F2: is expressed from the +1 reading frame, induces apoptosis by interaction with two mitochondrial proteins NS1: the NS1 protein is an interferon antagonist that blocks the activation of transcription factors and IFN-b-stimulated gene products, and binds to double-stranded RNA (dsRNA) to prevent the dsRNA-dependent activation of 2’-5’ oligo(A) synthetase, and the subsequent activation of RNase L; can block RIG-I, MDA5 and TLR-3,7 & 8 Prevention and control Antiviral drugs: M1: Adamantanes NA: Oseltamivir (Tamiflu) and Zanamivir, Peramivir CS-8958 (NA) Phase II T-705 (Nucleoside analogue) Phase III mAb against HA Vaccines: produced in allantoid fluid of embryonated chicken/cell culture Pandemrix (GSK) (dead vaccine) Focetria (Novartis) (dead vaccine) Celvapan (Baxter) (cell culture) Celtura (Behring) (cell culture) Live attenuated viruses yield higher humoral and cellular immune responses Thank you for your attention! “History” of the virus