title: Multiple amino acid substitutions involved in enhanced pathogenicity of LPAI H9N2 in mice.
abstract: Human infection of avian influenza H9N2 virus highlighted the need to better understand the mechanism of interspecies transmission. In this study, we generated mouse-adapted influenza virus (ma01) through serial lung-to-lung passages of a wild-type H9N2 (A/chicken/Hubei/01/1999). Ma01 caused highly lethal infection in mice with severe lung pathology and extended tissue tropism. Nine amino acid substitutions of ma01 were observed in five viral genes (those for PB2, PA, NA, M1, and NS1). Of these mutations, substitutes of PB2(627), PA(349), PA(605), NA(88), and NA(356) were absent in influenza H9N2. Furthermore, the targets of wild-type virus responding to mouse microRNA mmu-mir-1940 and mmu-mir-1904 were eliminated in ma01. The mutation PB2(627) of ma01 confirmed as a key virulence determinant of influenza H5N1 was responsible for the altered recognition of mmu-mir-1904. In addition, induction of IL-1β, IL-6, TNF-α, and IFN-β was found in significantly higher levels in ma01 infected mouse peripheral blood than parental strain. These results demonstrate that multiple amino acid substitutions and avoidance of microRNA recognitions may be essential for lethal infection and high speed of virus growth can outcompete the antiviral response of infected host.
authors: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
authors: Zongde
authors: Z
authors: Zhang
authors: Sishun
authors: S
authors: Hu
authors: Zili
authors: Z
authors: Li
authors: Xiliang
authors: X
authors: Wang
authors: Mei
authors: M
authors: Liu
authors: Zisheng
authors: Z
authors: Guo
authors: Shaowen
authors: S
authors: Li
authors: Yuncai
authors: Y
authors: Xiao
authors: Dingren
authors: D
authors: Bi
authors: Hui
authors: H
authors: Jin
mesh_terms: D000222:Adaptation, Physiological; D019943:Amino Acid Substitution; D000818:Animals; D001717:Birds; D016207:Cytokines / Q000096:biosynthesis; D005814:Genes, Viral; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D053127:Influenza A Virus, H9N2 Subtype / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D005585:Influenza in Birds / Q000635:transmission / Q000821:virology; D007251:Influenza, Human / Q000635:transmission / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000635:transmission* / Q000821:virology*; D014774:Virulence / Q000235:genetics
chemical_list: D016207:Cytokines; D035683:MicroRNAs