ACE2 from Pipistrellus abramus bats is a receptor for HKU5 coronaviruses
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1.
University of North Carolina at Chapel Hill
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2.
California Institute of Technology
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3.
Washington State University
Abstract
The merbecovirus subgenus of coronaviruses includes Middle East Respiratory Syndrome Coronavirus (MERS-CoV), a zoonotic pathogen transmitted from dromedary camels to humans that causes severe respiratory disease. Viral discovery efforts uncover hundreds of merbecoviruses in different species across multiple continents, but few are studied under laboratory conditions, leaving basic questions regarding their human threat potential unresolved. Viral entry into host cells is a critical step for transmission between hosts. Here, we develop and apply a scalable approach to assesses novel merbecovirus cell entry across the entire merbecovirus subgenus. Merbecoviruses are sorted into clades based on the receptor-binding domain of the spike glycoprotein. Receptor tropism is clade-specific, with the clade including MERS-CoV using DPP4 and multiple clades using ACE2, including HKU5 bat coronaviruses. Mutational analysis identifies possible structural limitations to HKU5 adaptability and a cryo-EM structure of the HKU5-20s spike trimer reveals only 'down' RBDs.
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Acknowledgement
We would like to thank Dr. Stephanie Seifert, Dr. Alex Cohen, Dr. Tyler Starr and Dr. Thomas Gallagher for providing valuable insights and comments on the work and manuscript. We also thank Andy DeLaitsch for his thoughtful and careful review of the manuscript. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH) under Award Numbers R01AI179720 to M.L., R01 AI167966 and CEIRS Contract 75N93021C00014 to R.S.B., P01AI100148 to P.J.B. and T32AI007025 to V.J. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
Funding
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH) under Award Numbers R01AI179720 to M.L., R01 AI167966 and CEIRS Contract 75N93021C00014 to R.S.B., P01AI100148 to P.J.B. and T32AI007025 to V.J. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
Contributions
N.J.C., Z.W., C.F., V.J., A.A., A.S., B.L.Y., and M.L. performed experiments, analysis. N.J.C., Z.W., V.J. and M.L. generated figures. P.J.B., R.B. and M.L. provided supervision and funding. M.L. developed the project concept and coordinated collaboration. All authors contributed to the manuscript and approved the final version of the text and figures.
Data Availability
Accession numbers for all spike sequences used in this study can be found in Table 1. Atomic models and cryo-EM maps generated from cryo-EM studies of the HKU5-20s spike have been deposited at the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) under accession codes PDB 9D4T and EMBD-46569, respectively. All plotted numerical values from the figures as well as uncropped westernblot images in this study are provided in the supplementary information/source data file. Source data are provided with this paper.
Conflict of Interest
RSB is a member of advisory boards for VaxArt, Takeda and Invivyd, and has collaborative projects with Gilead, J&J, and Hillevax, focused on unrelated projects. The remaining authors compare no competing interests.
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Additional details
- PMID
- 40436893
- PMCID
- PMC12119886
- National Institutes of Health
- R01AI179720
- National Institutes of Health
- R01AI167966
- National Institutes of Health
- CEIRS 75N93021C00014
- National Institutes of Health
- P01AI100148
- National Institutes of Health
- T32AI007025
- Submitted
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2024-12-17
- Accepted
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2025-05-20
- Caltech groups
- Division of Biology and Biological Engineering (BBE)
- Publication Status
- Published