title: Adaptive amino acid substitutions enhance the virulence of a novel human H7N9 influenza virus in mice.
abstract: To identify molecular features that confer enhanced H7N9 virulence in mammals, we independently generated three mouse-adapted variants of A/Shanghai/2/2013 (H7N9) by serial passage in mice. The mouse lethal doses (MLD50) of the mouse-adapted variants were reduced >1000-100000-fold when compared to the parental virus. Adapted variants displayed enhanced replication kinetics in vivo, and were capable of replicating in multiple organs. Analysis of adapted viral genomes revealed a total of 14 amino acid changes among the three variant viruses in the PA (T97I, K328R, P332T, and Q556R), HA (H3 numbering; A107T, R220I, L226Q, and R354K), NP (A284T and M352I), NA (M26I, N142S, and G389D), and M1 (M128R) proteins. Notably, many of these adaptive amino acid changes have been identified in naturally occurring H7 isolates. Our results identify amino acid substitutions that collectively enhance the ability of a human H7N9 virus to replicate and cause severe disease in mice.
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China; Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, People's Republic of China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Linna
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Tiecheng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Weiyang
authors.initials: W
authors.lastname: Sun
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China. Electronic address: qianj1970@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, People's Republic of China; Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China; Beijing Institute of Biotechnology, Beijing 100071, People's Republic of China. Electronic address: xiaxzh@cae.cn.
authors.forename: Xianzhu
authors.initials: X
authors.lastname: Xia
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D016679:Genome, Viral / Q000235:genetics; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D014774:Virulence / Q000235:genetics*; D014779:Virus Replication
keywords: Amino acid substitutions; H7N9 influenza virus; Mouse model; Virulence