title: Adaptive amino acid substitutions enhance the virulence of a reassortant H7N1 avian influenza virus isolated from wild waterfowl in mice.
abstract: H7 avian influenza viruses (AIVs) have caused a number of human infections, highlighting the pandemic potential of them. However, the factors that promote their replication in mammals remain poorly understood. Here, we generated mouse-adapted variants of a reassortant H7N1 virus to identify adaptive changes that confer enhanced virulence in mammals. The mouse lethal doses (MLD50) of the variants were reduced >10,000-fold compared to the parental virus. Adapted variants displayed enhanced replication kinetics in vitro and vivo, and were capable of replicating in multiple organs. Analysis of the variant virus genomes revealed amino acid changes in the PB2 (E627K), HA (H3 numbering; E114K, G205E, and G218E), and NA (S350N) proteins. Notably, some amino acid changes have been identified in natural H7 isolates. Our results implicate a number of amino acid substitutions that collectively enhance the ability of a wild bird-origin H7N1 AIV to replicate and cause severe disease in mice.
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, People's Republic of China; 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: 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: 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; Changchun Institute of Biological Products, Changchun 130122, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China; Liaoning Medical University, Jinzhou 121001, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Chai
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: Xiaolong
authors.initials: X
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: Jiao
authors.initials: J
authors.lastname: Guo
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: Kun
authors.initials: K
authors.lastname: Zhang
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: Na
authors.initials: N
authors.lastname: Feng
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: Xuexing
authors.initials: X
authors.lastname: Zheng
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: Hualei
authors.initials: H
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: Yongkun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, People's Republic of China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
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: Geng
authors.initials: G
authors.lastname: Huang
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: Songtao
authors.initials: S
authors.lastname: Yang
authors.affiliation: College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Changchun Institute of Biological Products, Changchun 130122, People's Republic of China. Electronic address: tyaxuemei@126.com.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
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. Electronic address: gaoyuwei@gmail.com.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, People's Republic of China; 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. Electronic address: xiaxianzhu1939@126.com.
authors.forename: Xianzhu
authors.initials: X
authors.lastname: Xia
mesh_terms: D000220:Adaptation, Biological; D019943:Amino Acid Substitution; D000818:Animals; D000835:Animals, Wild / Q000821:virology; D046090:Anseriformes / Q000821:virology*; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism; D057916:Influenza A Virus, H7N1 Subtype / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D005585:Influenza in Birds / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism; D016865:Reassortant Viruses / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity* / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014774:Virulence
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase; C487630:NA protein, influenza A virus; D009439:Neuraminidase
keywords: Adaptation; Avian influenza virus; H7N1; Mice; Wild waterfowl