title: Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity.
abstract: Two alleles of segment 8 (NS) circulate in nonchiropteran influenza A viruses. The A allele is found in avian and mammalian viruses, but the B allele is viewed as being almost exclusively found in avian viruses. This might reflect the fact that one or both of its encoded proteins (NS1 and NEP) are maladapted for replication in mammalian hosts. To test this, a number of clade A and B avian virus-derived NS segments were introduced into human H1N1 and H3N2 viruses. In no case was the peak virus titer substantially reduced following infection of various mammalian cell types. Exemplar reassortant viruses also replicated to similar titers in mice, although mice infected with viruses with the avian virus-derived segment 8s had reduced weight loss compared to that achieved in mice infected with the A/Puerto Rico/8/1934 (H1N1) parent. In vitro, the viruses coped similarly with type I interferons. Temporal proteomics analysis of cellular responses to infection showed that the avian virus-derived NS segments provoked lower levels of expression of interferon-stimulated genes in cells than wild type-derived NS segments. Thus, neither the A nor the B allele of avian virus-derived NS segments necessarily attenuates virus replication in a mammalian host, although the alleles can attenuate disease. Phylogenetic analyses identified 32 independent incursions of an avian virus-derived A allele into mammals, whereas 6 introductions of a B allele were identified. However, A-allele isolates from birds outnumbered B-allele isolates, and the relative rates of Aves-to-Mammalia transmission were not significantly different. We conclude that while the introduction of an avian virus segment 8 into mammals is a relatively rare event, the dogma of the B allele being especially restricted is misleading, with implications in the assessment of the pandemic potential of avian influenza viruses.
  
  
  
  Influenza A virus (IAV) can adapt to poultry and mammalian species, inflicting a great socioeconomic burden on farming and health care sectors. Host adaptation likely involves multiple viral factors. Here, we investigated the role of IAV segment 8. Segment 8 has evolved into two distinct clades: the A and B alleles. The B-allele genes have previously been suggested to be restricted to avian virus species. We introduced a selection of avian virus A- and B-allele segment 8s into human H1N1 and H3N2 virus backgrounds and found that these reassortant viruses were fully competent in mammalian host systems. We also analyzed the currently available public data on the segment 8 gene distribution and found surprisingly little evidence for specific avian host restriction of the B-clade segment. We conclude that B-allele segment 8 genes are, in fact, capable of supporting infection in mammals and that they should be considered during the assessment of the pandemic risk of zoonotic influenza A viruses.
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Turnbull
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Wise
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Marlynne Q
authors.initials: MQ
authors.lastname: Nicol
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Nikki
authors.initials: N
authors.lastname: Smith
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Dunfee
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Philippa M
authors.initials: PM
authors.lastname: Beard
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA Department of Pathology, Division of Virology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Brett W
authors.initials: BW
authors.lastname: Jagger
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ligertwood
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Hardisty
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, United Kingdom.
authors.forename: Haixia
authors.initials: H
authors.lastname: Xiao
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, United Kingdom.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Benton
authors.affiliation: The Centre for Virus Research, The University of Glasgow, Glasgow, United Kingdom.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Coburn
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joao A
authors.initials: JA
authors.lastname: Paulo
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, United Kingdom.
authors.forename: John W
authors.initials: JW
authors.lastname: McCauley
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
authors.forename: Jeffery K
authors.initials: JK
authors.lastname: Taubenberger
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Lycett
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Weekes
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.
authors.forename: Bernadette M
authors.initials: BM
authors.lastname: Dutia
authors.affiliation: Division of Infection and Immunity, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom paul.digard@roslin.ed.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Digard
mesh_terms: D000072283:A549 Cells; D000483:Alleles; D000818:Animals; D001717:Birds / Q000821:virology; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D057809:HEK293 Cells; D058507:Host Specificity / Q000235:genetics*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000821:virology; D007251:Influenza, Human / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D008322:Mammals / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000821:virology; D010802:Phylogeny; D016865:Reassortant Viruses / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics; D014774:Virulence / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
chemical_list: D014764:Viral Proteins