title: The PA-gene-mediated lethal dissemination and excessive innate immune response contribute to the high virulence of H5N1 avian influenza virus in mice.
abstract: Highly pathogenic H5N1 influenza A virus remains a substantial threat to public health. To understand the molecular basis and host mechanism for the high virulence of H5N1 viruses in mammals, we compared two H5N1 isolates which have similar genetic backgrounds but greatly differ in their virulence in mice. A/Chicken/Jiangsu/k0402/2010 (CK10) is highly pathogenic, whereas A/Goose/Jiangsu/k0403/2010 (GS10) is nonpathogenic. We first showed that CK10 elicited a more potent innate immune response than did GS10 in mouse lungs by increasing the number and expression levels of activated genes. We then generated a series of reassortants between the two viruses and evaluated their virulence in mice. Inclusion of the CK10 PA gene in the GS10 background resulted in a dramatic increase in virulence. Conversely, expression of the GS10 PA gene in the CK10 background significantly attenuated the virulence. These results demonstrated that the PA gene mainly determines the pathogenicity discrepancy between CK10 and GS10 in mice. We further determined that arginine (R) at position 353 of the PA gene contributes to the high virulence of CK10 in mice. The reciprocal substitution at position 353 in PA or the exchange of the entire PA gene largely caused the transfer of viral phenotypes, including virus replication, polymerase activity, and manipulation of the innate response, between CK10 and GS10. We therefore defined a novel molecular marker associated with the high virulence of H5N1 influenza viruses, providing further insights into the pathogenesis of H5N1 viruses in mammals.
authors.affiliation: Animal Infectious Disease Laboratory, School of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Hu
authors.forename: Zenglei
authors.initials: Z
authors.lastname: Hu
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Song
authors.forename: Min
authors.initials: M
authors.lastname: Gu
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Wang
authors.forename: Shunlin
authors.initials: S
authors.lastname: Hu
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Chen
authors.forename: Huimou
authors.initials: H
authors.lastname: Liu
authors.forename: Wenbo
authors.initials: W
authors.lastname: Liu
authors.forename: Sujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Daxin
authors.initials: D
authors.lastname: Peng
authors.forename: Xiufan
authors.initials: X
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002642:Chick Embryo; D005260:Female; D005814:Genes, Viral; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000821:virology; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D016601:RNA-Binding Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry / Q000235:genetics*; D016865:Reassortant Viruses / Q000472:pathogenicity; D014758:Viral Core Proteins / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics*; D014779:Virus Replication
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; C061290:PA protein, influenza viruses; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase