Madel Alfajaro Mia, Keeler Emma L, Li Ning, Catanzaro Nicholas J, Teng I-Ting, Zhao Zhe, Grunst Michael W, Yount Boyd, Schäfer Alexandra, Wang Danyi, Kim Arthur S, Synowiec Aleksandra, Peña-Hernández Mario A, Zepeda Samantha, Arinola Ridwan, Kaur Ramandeep, Menasche Bridget L, Wei Jin, Russell Gabriel A, Huck John, Song Jaewon, Ring Aaron, Iwasaki Akiko, Jangra Rohit K, Lee Sanghyun, Martinez David R, Mothes Walther, Uchil Pradeep D, Doench John G, Spaulding Alicen B, Baric Ralph S, Serebryannyy Leonid, Tsybovsky Yaroslav, Zhou Tongqing, Douek Daniel C, Wilen Craig B
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Nat Commun. 2025 Jul 24;16(1):6822. doi: 10.1038/s41467-025-61583-7.
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.
识别蝙蝠冠状病毒的受体对于溢出风险评估、对策制定和大流行防范至关重要。虽然中东呼吸综合征冠状病毒（MERS-CoV）利用二肽基肽酶4（DPP4）进入细胞，但许多与MERS相关的β冠状病毒的受体仍不清楚。蝙蝠梅氏冠状病毒HKU5先前已被证明在人类细胞中存在进入限制。通过使用假型病毒和全长病毒，我们发现HKU5利用伏翼蝙蝠ACE2作为受体，而不是人类ACE2或DPP4。对病毒-受体复合物的冷冻电子显微镜分析和基于结构的诱变揭示了一种与其他利用ACE2的冠状病毒不同的刺突蛋白与ACE2的相互作用。MERS-CoV疫苗血清对HKU5的中和作用较差，这为泛梅氏冠状病毒疫苗设计提供了信息。值得注意的是，HKU5还可以与美国水貂和白鼬的ACE2结合，表明鼬科动物是潜在的中间宿主。这些发现突出了梅氏冠状病毒受体使用的多样性，并强调了对蝙蝠和鼬科动物物种持续监测的必要性。
