title: Novel residues in the PA protein of avian influenza H7N7 virus affect virulence in mammalian hosts.
abstract: To evaluate the pathogenicity, a highly pathogenic avian influenza H7N7 virus (A/Netherlands/219/03) isolated from human was passaged in mice. A mutant virus (mH7N7) with attenuated virulence was isolated from mouse lung, which had a 3-log higher MLD50 than the wild-type virus (wH7N7). Sequence analysis and reverse genetics study revealed that mutations in PA account for the compromised viral replication in mammalian cells and mice. A mini-genome assay demonstrated that PA mutations P103H and S659L can cooperatively decrease polymerase activity. Actually, PA with double mutation P103H-S659L cannot sustain the generation of live virus by reverse genetics. Interestingly, the prior infection of mH7N7 virus provided mice with cross-protection against lethal challenge of other subtypes of influenza A virus including H1N1, H5N1 and H7N9. In conclusion, we demonstrated that PA mutations P103H and S659L can cooperatively reduce polymerase activity and viral replication in mammalian cells and attenuate pathogenicity in mice.
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong; State Key Laboratory of Emerging Infectious Diseases, Hong Kong; Research Centre of Infection and Immunology, Hong Kong.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Huiping
authors.initials: H
authors.lastname: Shuai
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Bosco Ho-Yin
authors.initials: BH
authors.lastname: Wong
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Lei
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Shuofeng
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong; State Key Laboratory of Emerging Infectious Diseases, Hong Kong; Research Centre of Infection and Immunology, Hong Kong. Electronic address: jiezhou@hku.hk.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong; State Key Laboratory of Emerging Infectious Diseases, Hong Kong; Research Centre of Infection and Immunology, Hong Kong; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong. Electronic address: kyyuen@hku.hk.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D053126:Influenza A Virus, H7N7 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D051379:Mice; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000821:virology; D011110:Polymorphism, Genetic; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics*; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics; D014779:Virus Replication
chemical_list: C061290:PA protein, influenza viruses; D014764:Viral Proteins; D037521:Virulence Factors; D012324:RNA-Dependent RNA Polymerase
keywords: H7N7 virus; Influenza A virus; Mutation; PA protein; Pathogenicity; Viral replication