Novel Polymerase Gene Mutations for Human Adaptation in Clinical Isolates of Avian H5N1 Influenza Viruses

PLoS Pathogens

Kazuyoshi Ikuta¹  Tomo Daidoji¹  Tatsuya Takagi¹  Kazuo Takahashi¹  Yasuo Suzuki²  Takaaki Nakaya²  Yasuha Arai³  Norihito Kawashita⁴  Yohei Watanabe⁵  Emad M. El-Gendy⁵  Tatsuo Shioda⁶  Madiha S. Ibrahim⁶ 

[1] Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto, Japan;Department of Microbiology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt;Department of Viral infection, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

关键词: Polymerases;    Microbial mutation;    H5N1;    Mutation databases;    Sequence databases;    Influenza viruses;    Influenza A virus;    Viral replication;   

DOI  :  10.1371/journal.ppat.1005583

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

A major determinant in the change of the avian influenza virus host range to humans is the E627K substitution in the PB2 polymerase protein. However, the polymerase activity of avian influenza viruses with a single PB2-E627K mutation is still lower than that of seasonal human influenza viruses, implying that avian viruses require polymerase mutations in addition to PB2-627K for human adaptation. Here, we used a database search of H5N1 clade 2.2.1 virus sequences with the PB2-627K mutation to identify other polymerase adaptation mutations that have been selected in infected patients. Several of the mutations identified acted cooperatively with PB2-627K to increase viral growth in human airway epithelial cells and mouse lungs. These mutations were in multiple domains of the polymerase complex other than the PB2-627 domain, highlighting a complicated avian-to-human adaptation pathway of avian influenza viruses. Thus, H5N1 viruses could rapidly acquire multiple polymerase mutations that function cooperatively with PB2-627K in infected patients for optimal human adaptation.

【 授权许可】

CC BY