Characterization of H5N1 Influenza Virus Quasispecies with Adaptive Hemagglutinin Mutations from Single-Virus Infections of Human Airway Cells

Author:

Watanabe Yohei12,Arai Yasuha12,Kawashita Norihito34,Ibrahim Madiha S.5,Elgendy Emad M.5,Daidoji Tomo1,Kajikawa Junichi1,Hiramatsu Hiroaki6,Sriwilaijaroen Nongluk67,Ono Takao8,Takagi Tatsuya4,Takahashi Kazuo9,Shioda Tatsuo2,Matsumoto Kazuhiko8,Suzuki Yasuo6,Nakaya Takaaki1

Affiliation:

1. Department of Infectious Diseases, Kyoto Prefectural School of Medicine, Kyoto, Japan

2. Department of Viral infections, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

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

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

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

6. College of Life and Health Sciences, Chubu University, Aichi, Japan

7. Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathumthani, Thailand

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

9. Department of Clinical Laboratory, International University of Health and Welfare Hospital, Tochigi, Japan

Abstract

ABSTRACT Transmission of avian influenza (AI) viruses to mammals involves phylogenetic bottlenecks that select small numbers of variants for transmission to new host species. However, little is known about the AI virus quasispecies diversity that produces variants for virus adaptation to humans. Here, we analyzed the hemagglutinin (HA) genetic diversity produced during AI H5N1 single-virus infection of primary human airway cells and characterized the phenotypes of these variants. During single-virus infection, HA variants emerged with increased fitness to infect human cells. These variants generally had decreased HA thermostability, an indicator of decreased transmissibility, that appeared to compensate for their increase in α2,6-linked sialic acid (α2,6 Sia) binding specificity and/or in the membrane fusion pH threshold, each of which is an advantageous mutational change for viral infection of human airway epithelia. An HA variant with increased HA thermostability also emerged but could not outcompete variants with less HA thermostability. These results provided data on HA quasispecies diversity in human airway cells. IMPORTANCE The diversity of the influenza virus quasispecies that emerges from a single infection is the starting point for viral adaptation to new hosts. A few studies have investigated AI virus quasispecies diversity during human adaptation using clinical samples. However, those studies could be appreciably affected by individual variability and multifactorial respiratory factors, which complicate identification of quasispecies diversity produced by selective pressure for increased adaptation to infect human airway cells. Here, we found that detectable HA genetic diversity was produced by H5N1 single-virus infection of human airway cells. Most of the HA variants had increased fitness to infect human airway cells but incurred a fitness cost of less HA stability. To our knowledge, this is the first report to characterize the adaptive changes of AI virus quasispecies produced by infection of human airway cells. These results provide a better perspective on AI virus adaptation to infect humans.

Funder

Takeda Science Foundation

Uehara Memorial Foundation

MEXT | Japan Society for the Promotion of Science

MEXT | Japan Science and Technology Agency

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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