OmniVira

HKU5 bat merbecoviruses engage bat and mink ACE2 as entry receptors.

Mia Madel Alfajaro1,2 Emma L Keeler1,3 Ning Li4 Nicholas J Catanzaro5 I-Ting Teng6 Zhe Zhao1,2 Michael W Grunst3 Boyd Yount5 Alexandra Schäfer5 Danyi Wang6 Arthur S Kim7,8 Aleksandra Synowiec1,2,9 Mario A Peña-Hernández1,2,3 Samantha Zepeda1,2 Ridwan Arinola10 Ramandeep Kaur10 Bridget L Menasche1,2 Jin Wei1,2 Gabriel A Russell2 John Huck2 Jaewon Song11 Aaron Ring2 Akiko Iwasaki2,12 Rohit K Jangra10 Sanghyun Lee11 David R Martinez2 Walther Mothes3 Pradeep D Uchil3 John G Doench13 Alicen B Spaulding6 Ralph S Baric5 Leonid Serebryannyy6 Yaroslav Tsybovsky4 Tongqing Zhou14 Daniel C Douek15 Craig B Wilen16,17
Affiliations 17 institutions
  1. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
  2. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  3. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
  4. Vaccine Research Center, Electron Microscopy Unit, Cancer Research Center Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  5. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
  6. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  7. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  8. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
  9. Malopolska Center of Biotechnology, Jagiellonian University, Krakow, Poland.
  10. Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
  11. Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
  12. Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  13. The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  14. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].
  15. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].
  16. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  17. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. [email protected].
PMID40707428 DOI10.1038/s41467-025-61583-7 Year2025 Journal Nature communications Nat Commun Languageeng Publication statusActive
Active Last checked 2026-09-30 03:30:40 Source: NCBI PubMed

Abstract

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.

Supporting text Virus Host Location
Angiotensin-Converting Enzyme 2 178 Chiroptera 376 Coronavirus 93 Mink 48 Receptors, Virus 208 Virus Internalization 100 Animals 1981 Cryoelectron Microscopy 37 Dipeptidyl Peptidase 4 32 HEK293 Cells 61 Humans 1455 Spike Glycoprotein, Coronavirus 276 ACE2 protein, human 87

Evidence records

2 total
Functional Mechanism
2 records · 1 evidence types
Evidence type Receptor Usage
2 records
OVE9592 Receptor Usage
Key finding

HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as its receptor for viral entry.

Virus
bat coronavirus HKU5
Host
Japanese house bat Pipistrellus abramus Experimental system human Homo sapiens Experimental system
Location
Not specified
Supporting text

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.

Method
pseudotyped virus assay | full-length virus infection assay
Receptors
ACE2 | DPP4