PA Mutations Inherited during Viral Evolution Act Cooperatively To Increase Replication of Contemporary H5N1 Influenza Virus with an Expanded Host Range

Author:

Arai Yasuha1,Kawashita Norihito23,Elgendy Emad Mohamed14,Ibrahim Madiha Salah4,Daidoji Tomo1,Ono Takao5,Takagi Tatsuya3,Nakaya Takaaki1,Matsumoto Kazuhiko5,Watanabe Yohei1ORCID

Affiliation:

1. Department of Infectious Diseases, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan

2. Faculty of Science and Engineering, Kindai University, Osaka, Japan

3. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

4. Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt

5. The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan

Abstract

Clade 2.2.1 avian influenza viruses (H5N1) are unique to Egypt and have caused the highest number of human H5N1 influenza cases worldwide, presenting a serious global public health threat. These viruses may have the greatest evolutionary potential for adaptation from avian hosts to human hosts. Using a comprehensive phylogenetic approach, we identified several novel clade 2.2.1 virus polymerase mutations that increased viral replication in vitro in human cells and in vivo in mice. These mutations were in the polymerase PA subunit and acted cooperatively with the E627K mutation in the PB2 polymerase subunit to provide higher replication in contemporary clade 2.2.1.2 viruses than in ancestral clade 2.2.1 viruses. These data indicated that ongoing clade 2.2.1 dissemination in the field has driven PA mutations to modify viral replication to enable host range expansion, with a higher public health risk for humans.

Funder

Sasakawa Scientific Research Foundation

Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care

MEXT | Japan Society for the Promotion of Science

MEXT | Japan Science and Technology Agency

Takeda Science Foundation

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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