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). Sequ...

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Published in:Virology (New York, N.Y.) N.Y.), 2016-11, Vol.498, p.1-8
Main Authors: Zhao, Hanjun, Chu, Hin, Zhao, Xiaoyu, Shuai, Huiping, Wong, Bosco Ho-Yin, Wen, Lei, Yuan, Shuofeng, Zheng, Bo-Jian, Zhou, Jie, Yuen, Kwok-Yung
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Cell Line
Cells, Cultured
Female
H7N7 virus
Host-Pathogen Interactions
Humans
Infectious Disease
Influenza A virus
Influenza A Virus, H7N7 Subtype - genetics
Influenza A Virus, H7N7 Subtype - pathogenicity
Mice
Mutation
Orthomyxoviridae Infections - mortality
Orthomyxoviridae Infections - virology
PA protein
Pathogenicity
Polymorphism, Genetic
RNA Replicase - genetics
Viral Load
Viral Proteins - genetics
Viral replication
Virulence - genetics
Virulence Factors - genetics
Virus Replication
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Summary: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.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2016.08.004