title: Multiple amino acid substitutions involved in the adaptation of H6N1 avian influenza virus in mice.
abstract: H6N1 avian influenza viruses (AIVs) are one of the most abundantly detected avian influenza virus subtype, and a human H6N1 infection case has been reported in 2013. H6N1 AIVs may pose a potential human risk, however, the factors that promote the replication of H6N1 viruses in mammals remain poorly understood. Here, we generated mouse-adapted variants of a H6N1 virus (A/Mallard/SanJiang/275/2007) to identify adaptive changes that confer enhanced virulence to H6N1 viruses in mammals. After eight sequential passages in mice, the mouse lethal doses (MLD50) of the variants were reduced >1000-fold compared to the parental virus. We found that the variants displayed the greatest enhancement of replication in vitro and in vivo, and also were capable of replicating in the brains of infected mice. These observations suggest that enhanced growth characteristics and modified cell tropism may contribute to increased virulence of H6N1 AIVs in mice. Sequencing of the variants revealed amino acid changes in the PB2 (E627K), PA (T97I), and HA (N394T) proteins. Our results suggest that these mutations involved in the enhancement of the ability of H6N1 virus to efficient replicate and cause severe disease in mammals.
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 of 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 of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China; Dairy Cattle Research Center, Shandong Academy of Agricultural Sciences, Jinan 250132, People's Republic of China.
authors.forename: Kaihui
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute of 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 of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute of 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 of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Songtao
authors.initials: S
authors.lastname: Yang
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute of 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 of 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 of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
authors.forename: Hualei
authors.initials: H
authors.lastname: Wang
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: 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: 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 of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China.
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 of Academy of Military Medical Sciences, Changchun 130122, 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 of Academy of Military Medical Sciences, Changchun 130122, People's Republic of China. Electronic address: xiaxianzhu1939@126.com.
authors.forename: Xianzhu
authors.initials: X
authors.lastname: Xia
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D004372:Ducks / Q000821:virology*; D005260:Female; D009980:Influenza A virus / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D005585:Influenza in Birds / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009976:Orthomyxoviridae Infections / Q000821:virology*; D017422:Sequence Analysis, DNA; D014764:Viral Proteins / Q000235:genetics*; D014774:Virulence
chemical_list: D014764:Viral Proteins
keywords: Adaptation; Avian influenza virus; H6N1; Human; Mice