title: Amino acid substitutions V63I or A37S/I61T/V63I/V100A in the PA N-terminal domain increase the virulence of H7N7 influenza A virus.
abstract: The PA N-terminal domain (PA-Nter) is essential for viral transcription and replication. Here we identified PA-Nter substitutions A37S, I61T, V63I and V100A in recently emerged avian influenza A viruses (IAVs) with potential effect on virus pathogenicity and/or host adaptation. We introduced the identified PA-Nter substitutions into avian H7N7 IAV by reverse genetics. Our results showed that single substitution V63I and combined substitutions, I61T/V63I and A37S/I61T/V63I/V100A (Mfour), significantly increased virus growth capacity in mammalian cells. Meanwhile, these substitutions conferred higher virus transcription/replication capacity by producing more mRNA, cRNA and vRNA. Consistently, the polymerase activity and the endonuclease activity were enhanced by these PA-Nter substitutions. Notably, substitutions V63I and Mfour strongly increased virus replication and virulence in mice. Collectively, our findings demonstrated that the PA-Nter substitutions V63I and Mfour enhanced IAV pathogenicity through modification of the polymerase activity and the endonuclease activity, which added to the evolving knowledge of IAV virulence determinants.
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kailash
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Cun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Shuofeng
authors.initials: S
authors.lastname: Yuan
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Billy K C
authors.initials: BK
authors.lastname: Chow
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001717:Birds; D002478:Cells, Cultured; D006801:Humans; D053126:Influenza A Virus, H7N7 Subtype / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000821:virology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry*; D014774:Virulence
chemical_list: D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins