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p resented 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.

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presented by Jan Haas

Institute for Immunology

influenzaviruses orthomyxoviridae
Influenzaviruses: Orthomyxoviridae

16 Haemagglutinin

9 Neuraminidase

- types

3 Polymerase Subunits


Nuclear Export Protein (NEP)

Matrix Protein (M1)

Ion Channel Protein (M2)

Interferon Antagonist (NS1)

PB1-F2 Protein

the viral life cycle
The viral life cycle
  • (-) RNA virus
  • enveloped
  • Influenza A responsible for pandemic outbreaks
  • spread via aerosols and droplets
Genetic Relationships among Human and Relevant Swine Influenza Viruses, 1918–2009.

Yellow arrows reflect exportation of one or more genes from the avian influenza A virus gene pool. The dashed red arrow indicates a period without circulation. Solid red arrows indicate the evolutionary paths of human influenza virus lineages; solid blue arrows, of swine influenza virus lineages; and the blue-to-red arrow, of a swine-origin human influenza virus. All influenza A viruses contain eight genes that encode the following proteins (shown from top to bottom within each virus): polymerase PB2, polymerase PB1, polymerase PA, hemagglutinin (HA), nuclear protein (NP), neuraminidase (NA), matrix proteins (M), and nonstructural proteins (NS). The genes of the 1918 human and swine H1N1 and the 1979 H1N1 influenza A viruses were all recently descended from avian influenza A genes, and some have been “donated” to the pandemic human H1N1 strain.

  • ‘Russian’ influenza (H1N1, 1977)
  • the re-emerging H1N1 virus did not replace the H3N2 viruses circulating at the time
  • both subtypes are co-circulating in humans to this day
  • reassortment between viruses of these subtypes resulted in the emergence of H1N2 viruses in human populations in 2001
  • H1N2 viruses have since disappeared.
  • ‘Spanish’ influenza (H1N1, 1918-1919)
  • mortality pattern unusual: young adults
  • restricted to the respiratory tract, lack of systemic infection
  • most patients died of bacterial pneumonia, some as well of viral pneumonia
  • aberrant innate immune responses contributing to its virulence
  • ‘Asian’ influenza (H2N2, 1957-1958)
  • was caused by a human/avian reassortant that introduced avian virus H2 HA and N2 NA genes into human populations
  • furthermore, the Asian influenza virus also possessed a PB1 gene of avian virus origin
  • ‘H5N1’ influenza (1997-2003)
  • Hong Kong: highly pathogenic avian virus
  • six fatalities, marked the first reported fatal infections of humans with avian influenza viruses
  • after a period of local and sporadic outbreaks, a new outbreak started in 2003
  • sustained human-to-human infection has not occurred
  • H5N1 viruses are characterized by a high mortality rate but inefficient spread among humans
  •  in contrast, S-OIVs seem to spread efficiently among humans but have caused a limited number of fatal infections
  • ‘Hongkong’ influenza (H3N2, 1968-1970)
  • viruses of the H2N2 subtype were replaced by another human/avian reassortant that possessed an H3 HA gene of avian virus origin
  • again, the PB1 gene of the pandemic virus was derived from an avian virus
  • ‘S-OIV H1N1’ influenza (2009)
  • S-OIVs probably resulted from the reassortment of recent North American H3N2 and H1N2 swine viruses (that is, avian/human/swine ‘triple’ reassortant viruses) with Eurasian avian-like swine viruses
  • S-OIVs possess: PB2 and PA genes of North American avian virus origin, a PB1 gene of human H3N2 virus origin, HA (H1), NP, and NS genes of classical swine virus origin, and NA (N1) and M genes of Eurasian avian-like swine virus origin (hence their original description as ‘quadruple’ reassortants)
role of ha in viral pathogenicity
Role of HA in viral pathogenicity
  • Receptor distribution on host cells:
  • human influenza preferentially bind to sialic acid that is linked to galactose by an a2,6-linkage (SAa2,6Gal)
  • this preference is matched by SAa2,6Gal on epithelial cells in the human trachea
  • in 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)
  • surprisingly H5N1 binds preferentially to SAa2,3Gal
  • studies 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
  • Low pathogenic viruses possess a Arg residue at the cleavage site
  • highly 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
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
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