Molecular basis of sarbecovirus evolution and receptor tropism in natural hosts, potential intermediate hosts, and humans

Affiliations

¹ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
³ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
⁴ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁵ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
⁶ Department of Life Sciences, Faculty of Natural Science, Imperial College London, London, UK.
⁷ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁸ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan; International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Collaboration Unit for Infection, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore. Electronic address: keisato@g.ecc.u-tokyo.ac.jp.

PMID: 40934083
DOI: 10.1016/j.celrep.2025.116220

Free article

Molecular basis of sarbecovirus evolution and receptor tropism in natural hosts, potential intermediate hosts, and humans

Yusuke Kosugi et al. Cell Rep. 2025.

Free article

. 2025 Sep 23;44(9):116220.

doi: 10.1016/j.celrep.2025.116220. Epub 2025 Sep 9.

Authors

Affiliations

¹ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
³ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
⁴ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁵ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
⁶ Department of Life Sciences, Faculty of Natural Science, Imperial College London, London, UK.
⁷ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁸ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan; International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Collaboration Unit for Infection, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore. Electronic address: keisato@g.ecc.u-tokyo.ac.jp.

PMID: 40934083
DOI: 10.1016/j.celrep.2025.116220

Abstract

The spike protein of many sarbecoviruses binds to the angiotensin-converting enzyme 2 (ACE2) receptor and facilitates viral entry. The diversification of the sarbecovirus spike gene and the mammalian ACE2 gene suggests that sarbecoviruses and their hosts have co-evolved, and the genetic diversity in these genes affects the host tropism of sarbecoviruses. Better comprehending the evolutionary potential of sarbecoviruses can lead to preparedness for the next pandemic. However, the host tropism of sarbecoviruses is not fully understood. Here, we performed pseudovirus infection assays using 53 sarbecoviruses and ACE2s from 17 mammals to elucidate the ACE2 tropism of sarbecoviruses in natural hosts, potential intermediate hosts, and humans. We determined the factors responsible for the ACE2 tropism of sarbecoviruses through structural and phylogenetic analyses and infection experiments, revealing which substitutions can expand the host range of sarbecoviruses. These results highlight the mechanisms modulating host tropism throughout sarbecovirus evolution.

Keywords: ACE2; CP: Microbiology; SARS-CoV-2; evolution; sarbecovirus; spillover.

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Conflict of interest statement

Declaration of interests S.L. has received consulting fees from EcoHealth Alliance. J.I. has received consulting fees and honoraria for lectures from Takeda Pharmaceutical Co. Ltd. and AstraZeneca. K.S. has received consulting fees from Moderna Japan Co., Ltd. and Takeda Pharmaceutical Co. Ltd. and honoraria for lectures from Moderna Japan Co., Ltd., Shionogi & Co., Ltd., and AstraZeneca. All authors have submitted the International Committee of Medical Journal Editors (ICMJE) Form for disclosure of potential conflicts of interest.

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Molecular basis of sarbecovirus evolution and receptor tropism in natural hosts, potential intermediate hosts, and humans

Affiliations

Molecular basis of sarbecovirus evolution and receptor tropism in natural hosts, potential intermediate hosts, and humans

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous