title: PB2 substitutions V598T/I increase the virulence of H7N9 influenza A virus in mammals.
abstract: PB2 is one of the subunits of the influenza A virus (IAV) polymerase complex. By bioinformatics analysis we identified PB2 substitutions at positions 389 and 598 among IAV isolates from humans, which might associate with viral pathogenicity. To evaluate the biological significance of these substitutions, PB2-K389R and -V598T/I mutant viruses of avian H7N9 IAVs were generated by reverse genetics. Compared to the wild type, the mutant viruses displayed an enhanced growth capacity in human and mammalian cells. Meanwhile, they presented increased transcription and replication by producing higher levels of viral mRNA, cRNA and vRNA. Minireplicon assays indicated that the polymerase activity was elevated by these substitutions. Notably, the PB2-V598T/I substitutions substantially increased virus replication and virulence in mice. Together, we demonstrated that the substitutions PB2-V598T/I contributed to higher IAV replication and virulence in mammals, which added to the knowledge of IAV virulence determinants and benefited the surveillance of IAVs.
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Shuofeng
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Kailash
authors.initials: K
authors.lastname: Singh
authors.affiliation: College of Life Science, Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: hinchu@hku.hk.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: bzheng@hkucc.hku.hk.
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001717:Birds; D005260:Female; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D005585:Influenza in Birds / Q000821:virology; D007251:Influenza, Human / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014774:Virulence; D014779:Virus Replication
chemical_list: C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase
keywords: Influenza A virus; PB2; PB2-K389R; PB2-V598T/I; Virulence