HKU5 bat merbecoviruses engage bat and mink ACE2 as entry receptors

Mia Madel Alfajaro, Emma L. Keeler, Ning Li, Nicholas J. Catanzaro, I-Ting Teng, Zhe Zhao, Michael W. Grunst, Boyd Yount, Alexandra Schäfer, Danyi Wang, Arthur S. Kim, Aleksandra Synowiec, Mario A. Peña-Hernández, Samantha Zepeda, Ridwan Arinola, Ramandeep Kaur, Bridget L. Menasche, Jin Wei, Gabriel A. Russell, John Huck, Jaewon Song, Aaron Ring, Akiko Iwasaki, Rohit K. Jangra, Sanghyun Lee, David R. Martinez, Walther Mothes, Pradeep D. Uchil, John G. Doench, Alicen B. Spaulding, Ralph S. Baric, Leonid Serebryannyy, Yaroslav Tsybovsky, Tongqing Zhou (), Daniel C. Douek () and Craig B. Wilen ()
Additional contact information
Mia Madel Alfajaro: Yale University School of Medicine
Emma L. Keeler: Yale University School of Medicine
Ning Li: Frederick National Laboratory for Cancer Research
Nicholas J. Catanzaro: University of North Carolina
I-Ting Teng: National Institutes of Health
Zhe Zhao: Yale University School of Medicine
Michael W. Grunst: Yale University School of Medicine
Boyd Yount: University of North Carolina
Alexandra Schäfer: University of North Carolina
Danyi Wang: National Institutes of Health
Arthur S. Kim: The Scripps Research Institute
Aleksandra Synowiec: Yale University School of Medicine
Mario A. Peña-Hernández: Yale University School of Medicine
Samantha Zepeda: Yale University School of Medicine
Ridwan Arinola: Louisiana State University Health Sciences Center-Shreveport
Ramandeep Kaur: Louisiana State University Health Sciences Center-Shreveport
Bridget L. Menasche: Yale University School of Medicine
Jin Wei: Yale University School of Medicine
Gabriel A. Russell: Yale University School of Medicine
John Huck: Yale University School of Medicine
Jaewon Song: Brown University
Aaron Ring: Yale University School of Medicine
Akiko Iwasaki: Yale University School of Medicine
Rohit K. Jangra: Louisiana State University Health Sciences Center-Shreveport
Sanghyun Lee: Brown University
David R. Martinez: Yale University School of Medicine
Walther Mothes: Yale University School of Medicine
Pradeep D. Uchil: Yale University School of Medicine
John G. Doench: The Broad Institute of Harvard and MIT
Alicen B. Spaulding: National Institutes of Health
Ralph S. Baric: University of North Carolina
Leonid Serebryannyy: National Institutes of Health
Yaroslav Tsybovsky: Frederick National Laboratory for Cancer Research
Tongqing Zhou: National Institutes of Health
Daniel C. Douek: National Institutes of Health
Craig B. Wilen: Yale University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61583-7

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