Residues in the PB2 and PA genes contribute to the pathogenicity of avian H7N3 influenza A virus in DBA/2 mice.
Replication and transmission of avian influenza virus in humans poses a pandemic threat. The molecular determinants that facilitate this process are not well understood. We used DBA/2 mice to identify viral factors that mediate the difference in pathogenesis between a virulent (H7N3) and a non-virulent (H7N9) avian influenza virus from North America. In vitro and in vivo characterization of reassortant viruses identified the PB2 and PA polymerase genes as major determinants of H7N3 pathogenesis. Analysis of individual residues in the PB2 and PA genes identified position 358 (E358V) in PB2 and positions 190 (P190S) and 400 (Q400P) in PA that reduced the virulence of H7N3 virus. The E358V and P190S substitutions also caused reduced inflammation after infection. Our results suggest that specific residues in the polymerase proteins PB2 and PA are important for replication and virulence of avian influenza viruses in a mammalian host.
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Brittany L
BL
DesRochers
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Rita E
RE
Chen
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Anshu P
AP
Gounder
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Amelia K
AK
Pinto
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Traci
T
Bricker
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Camille N
CN
Linton
Department of Infectious Diseases, St. Jude Children׳s Research Hospital, Memphis, TN 38105, USA.
Corianne D
CD
Rogers
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Graham D
GD
Williams
Department of Infectious Diseases, St. Jude Children׳s Research Hospital, Memphis, TN 38105, USA.
Richard J
RJ
Webby
Departments of Internal Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address: jboon@dom.wustl.edu.
Adrianus C M
AC
Boon
D000595:Amino Acid Sequence; D000596:Amino Acids; D000818:Animals; D017124:Conserved Sequence; D057920:Influenza A Virus, H7N3 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D064766:Influenza A Virus, H7N9 Subtype / Q000235:genetics / Q000472:pathogenicity; D051379:Mice; D008811:Mice, Inbred DBA; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000821:virology*; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry / Q000235:genetics*; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity; D012720:Severity of Illness Index; D019562:Viral Load; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics*; D037521:Virulence Factors / Q000235:genetics; D014779:Virus Replication
D000596:Amino Acids; C061290:PA protein, influenza viruses; C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D037521:Virulence Factors; D012324:RNA-Dependent RNA Polymerase
Avian influenza virus; DBA/2J; H7 subtype; Pathogenesis