title: PB2-E627K and PA-T97I substitutions enhance polymerase activity and confer a virulent phenotype to an H6N1 avian influenza virus in mice.
abstract: H6N1 avian influenza viruses (AIVs) may pose a potential human risk as suggested by the first documented naturally-acquired human H6N1 virus infection in 2013. Here, we set out to elucidate viral determinants critical to the pathogenesis of this virus using a mouse model. We found that the recombinant H6N1 viruses possessing both the PA-T97I and PB2-E627K substitutions displayed the greatest enhancement of replication in vitro and in vivo. Polymerase complexes possessing either PB2-E627K, PA-T97I, and PB2-E627K/PA-T97I displayed higher virus polymerase activity when compared to the wild-type virus, which may account for the increased replication kinetics and enhanced virulence of variant viruses. Our results demonstrate that PB2-E627K and PA-T97I enhance the ability of H6N1 virus to replicate and cause disease in mammals. Influenza surveillance efforts should include scrutiny of these regions of PB2 and PA because of their impact on the increased virulence of H6N1 AIVs in mice.
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, PLA 666 Liuyingxi Street, 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, Academy of Military Medical Sciences, PLA 666 Liuyingxi Street, 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: 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, PLA 666 Liuyingxi Street, 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, PLA 666 Liuyingxi Street, Changchun 130122, People׳s Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xin
authors.affiliation: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, People׳s Republic of China.
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, PLA 666 Liuyingxi Street, 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, Academy of Military Medical Sciences, PLA 666 Liuyingxi Street, 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, PLA 666 Liuyingxi Street, 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, Academy of Military Medical Sciences, PLA 666 Liuyingxi Street, 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, Academy of Military Medical Sciences, PLA 666 Liuyingxi Street, 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, PLA 666 Liuyingxi Street, 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, PLA 666 Liuyingxi Street, Changchun 130122, People׳s Republic of China.
authors.forename: Hualei
authors.initials: H
authors.lastname: Wang
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, PLA 666 Liuyingxi Street, Changchun 130122, People׳s Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, People׳s Republic of China.
authors.forename: Hualan
authors.initials: H
authors.lastname: Chen
authors.affiliation: College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People׳s Republic of China. Electronic address: yuping_hua@126.com.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, PLA 666 Liuyingxi Street, Changchun 130122, People׳s Republic of China. Electronic address: gaoyuwei@gmail.com.
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, PLA 666 Liuyingxi Street, 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. Electronic address: xiaxianzhu1939@126.com.
authors.forename: Xianzhu
authors.initials: X
authors.lastname: Xia
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006801:Humans; D009980:Influenza A virus / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D056189:Viral Tropism / Q000235:genetics / Q000502:physiology; D014774:Virulence; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; D012321:DNA-Directed RNA Polymerases
keywords: Avian influenza virus; H6N1; Mice; Pathogenicity