HKU5 bat merbecoviruses engage bat and mink ACE2 as entry receptors
Identifying receptors for bat coronaviruses is critical for spillover risk assessment, countermeasure development, and pandemic preparedness. While Middle East respiratory syndrome coronavirus (MERS-CoV) uses DPP4 for entry, the receptors of many MERS-related betacoronaviruses remain unknown. The bat merbecovirus HKU5 was previously shown to have an entry restriction in human cells. Using both pseudotyped and full-length virus, we show that HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as a receptor. Cryo-electron microscopy analysis of the virus-receptor complex and structure-guided mutagenesis reveal a spike and ACE2 interaction that is distinct from other ACE2-using coronaviruses. MERS-CoV vaccine sera poorly neutralize HKU5 informing pan-merbecovirus vaccine design. Notably, HKU5 can also engage American mink and stoat ACE2, revealing mustelids as potential intermediate hosts. These findings highlight the versatility of merbecovirus receptor use and underscore the need for continued surveillance of bat and mustelid species.
Authors
- Tongqing Zhou (ORCID: https://orcid.org/0000-0002-3935-4637)
- Michael W. Grunst (ORCID: https://orcid.org/0000-0002-8575-8026)
- Danyi Wang (ORCID: https://orcid.org/0009-0008-0820-7037)
- Akiko Iwasaki (ORCID: https://orcid.org/0000-0002-7824-9856)
- Aleksandra Synowiec (ORCID: https://orcid.org/0000-0001-9846-6922)
- Ralph Steven Baric (ORCID: https://orcid.org/0000-0001-6827-8701)
- John D. Huck
- Walther Mothes
- Gabriel A Russell
- Arthur S. Kim (ORCID: https://orcid.org/0000-0003-4101-6642)
- Daniel C. Douek (ORCID: https://orcid.org/0000-0001-5575-8634)
- Alicen B. Spaulding (ORCID: https://orcid.org/0000-0002-4687-3259)
- Pradeep D. Uchil (ORCID: https://orcid.org/0000-0002-7236-858X)
- John G. Doench (ORCID: https://orcid.org/0000-0002-3707-9889)
- Boyd L. Yount (ORCID: https://orcid.org/0000-0002-6099-8429)
- Nicholas Catanzaro (ORCID: https://orcid.org/0000-0002-0210-8440)
- Aaron M. Ring (ORCID: https://orcid.org/0000-0003-3699-2446)
- Leonid Serebryannyy (ORCID: https://orcid.org/0000-0003-0213-1779)
- Mia Madel Alfajaro (ORCID: https://orcid.org/0000-0002-6402-2730)
- Rohit K. Jangra (ORCID: https://orcid.org/0000-0002-3119-0869)
- Emma L. Keeler (ORCID: https://orcid.org/0000-0002-8768-0592)
- Mario A. Peña-Hernández
- Yaroslav Tsybovsky (ORCID: https://orcid.org/0000-0002-2159-5248)
- Samantha K. Zepeda (ORCID: https://orcid.org/0000-0003-0005-9793)
- Jaewon Song (ORCID: https://orcid.org/0000-0002-9387-1942)
- Bridget L. Menasché (ORCID: https://orcid.org/0000-0003-3520-2422)
- Jin Wei (ORCID: https://orcid.org/0000-0002-2832-1610)
- Alexandra Schäfer (ORCID: https://orcid.org/0000-0002-4760-4923)
- Craig B. Wilen (ORCID: https://orcid.org/0000-0003-2495-9403)
- I‐Ting Teng (ORCID: https://orcid.org/0000-0002-4704-7100)
- Sanghyun Lee (ORCID: https://orcid.org/0000-0002-0736-1648)
- Ramandeep Kaur (ORCID: https://orcid.org/0000-0002-8850-7011)
- Zhe Zhao (ORCID: https://orcid.org/0000-0002-4119-0504)
- Ning Li (ORCID: https://orcid.org/0009-0007-5202-2075)
- David R. Martinez (ORCID: https://orcid.org/0000-0002-1689-5529)
- Ridwan Arinola
Institutions
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Scripps Research Institute (US)
- Jagiellonian University (PL)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- Brown University (US)
- Yale University (US)
- Frederick National Laboratory for Cancer Research (US)
- National Institute of Allergy and Infectious Diseases (US)
- Louisiana State University Health Sciences Center Shreveport (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1038/s41467-025-61583-7
- Citations
- 2
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- U.S. Department of Health and Human Services
- Life Sciences Research Foundation
- Open Philanthropy Project
- National Institutes of Health
- National Cancer Institute