Cell . Bat-infecting merbecovirus HKU5-CoV lineage 2 can use human ACE2 as a cell entry receptor

[tetano]

Cell


. 2025 Feb 12:S0092-8674(25)00144-8.
doi: 10.1016/j.cell.2025.01.042. Online ahead of print. Bat-infecting merbecovirus HKU5-CoV lineage 2 can use human ACE2 as a cell entry receptor

Jing Chen[SUP] 1 [/SUP], Wei Zhang[SUP] 2 [/SUP], Yang Li[SUP] 1 [/SUP], Chen Liu[SUP] 3 [/SUP], Tianyi Dong[SUP] 4 [/SUP], Huiyu Chen[SUP] 2 [/SUP], Chunguang Wu[SUP] 4 [/SUP], Jia Su[SUP] 4 [/SUP], Bei Li[SUP] 1 [/SUP], Wei Zhang[SUP] 1 [/SUP], Ben Hu[SUP] 1 [/SUP], Jingkun Jia[SUP] 4 [/SUP], Cheng-Bao Ma[SUP] 3 [/SUP], Yan Zhu[SUP] 1 [/SUP], Xiangyang He[SUP] 5 [/SUP], Ang Li[SUP] 2 [/SUP], Kaiyi Pan[SUP] 4 [/SUP], Haofeng Lin[SUP] 6 [/SUP], Zishuo Guo[SUP] 4 [/SUP], Cong Li[SUP] 7 [/SUP], Libiao Zhang[SUP] 8 [/SUP], Huan Yan[SUP] 9 [/SUP], Peng Zhou[SUP] 10 [/SUP], Wei Peng[SUP] 11 [/SUP], Zheng-Li Shi[SUP] 12 [/SUP]



Affiliations

• PMID: 39970913
• DOI: 10.1016/j.cell.2025.01.042

Abstract

Merbecoviruses comprise four viral species with remarkable genetic diversity: MERS-related coronavirus, Tylonycterisbat coronavirus HKU4, Pipistrellusbat coronavirus HKU5, and Hedgehog coronavirus 1. However, the potential human spillover risk of animal merbecoviruses remains to be investigated. Here, we reported the discovery of HKU5-CoV lineage 2 (HKU5-CoV-2) in bats that efficiently utilize human angiotensin-converting enzyme 2 (ACE2) as a functional receptor and exhibits a broad host tropism. Cryo-EM analysis of HKU5-CoV-2 receptor-binding domain (RBD) and human ACE2 complex revealed an entirely distinct binding mode compared with other ACE2-utilizing merbecoviruses with RBD footprint largely shared with ACE2-using sarbecoviruses and NL63. Structural and functional analyses indicate that HKU5-CoV-2 has a better adaptation to human ACE2 than lineage 1 HKU5-CoV. Authentic HKU5-CoV-2 infected human ACE2-expressing cell lines and human respiratory and enteric organoids. This study reveals a distinct lineage of HKU5-CoVs in bats that efficiently use human ACE2 and underscores their potential zoonotic risk.

Keywords: bat; cryo-EM analysis; host tropism; human ACE2; lineage 2 HKU5; merbecovirus; viral isolation.

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[sharon sanders]

Affiliations
1) Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
2) Guangzhou National Laboratory, No. 9 XingDaoHuanBei Road, Guangzhou International Bio Island, Guangzhou, China
3) The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
4) State Key Laboratory of Virology and Biosafety, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
5) University of Chinese Academy of Sciences, Beijing, China
6) Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
7) Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
8) These authors contributed equally
9) Lead contact​