Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Qing Xiong, Lei Cao, Chengbao Ma, M. Alejandra Tortorici, Chen Liu, Junyu Si, Peng Liu, Mengxue Gu, Alexandra C. Walls, Chunli Wang, Lulu Shi, Fei Tong, Meiling Huang, Jing Li, Chufeng Zhao, Chao Shen, Yu Chen, Huabin Zhao, Ke Lan, Davide Corti, David Veesler (), Xiangxi Wang () and Huan Yan ()
Additional contact information
Qing Xiong: Wuhan University
Lei Cao: Chinese Academy of Sciences
Chengbao Ma: Wuhan University
M. Alejandra Tortorici: University of Washington
Chen Liu: Wuhan University
Junyu Si: Wuhan University
Peng Liu: Wuhan University
Mengxue Gu: Wuhan University
Alexandra C. Walls: University of Washington
Chunli Wang: Wuhan University
Lulu Shi: Wuhan University
Fei Tong: Wuhan University
Meiling Huang: Wuhan University
Jing Li: Wuhan University
Chufeng Zhao: Wuhan University
Chao Shen: Wuhan University
Yu Chen: Wuhan University
Huabin Zhao: Wuhan University
Ke Lan: Wuhan University
Davide Corti: Humabs BioMed SA, subsidiary of Vir Biotechnology
David Veesler: University of Washington
Xiangxi Wang: Chinese Academy of Sciences
Huan Yan: Wuhan University

Nature, 2022, vol. 612, issue 7941, 748-757

Abstract: Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) and several bat coronaviruses use dipeptidyl peptidase-4 (DPP4) as an entry receptor1–4. However, the receptor for NeoCoV—the closest known MERS-CoV relative found in bats—remains unclear5. Here, using a pseudotype virus entry assay, we found that NeoCoV and its close relative, PDF-2180, can efficiently bind to and use specific bat angiotensin-converting enzyme 2 (ACE2) orthologues and, less favourably, human ACE2 as entry receptors through their receptor-binding domains (RBDs) on the spike (S) proteins. Cryo-electron microscopy analysis revealed an RBD–ACE2 binding interface involving protein–glycan interactions, distinct from those of other known ACE2-using coronaviruses. We identified residues 337–342 of human ACE2 as a molecular determinant restricting NeoCoV entry, whereas a NeoCoV S pseudotyped virus containing a T510F RBD mutation efficiently entered cells expressing human ACE2. Although polyclonal SARS-CoV-2 antibodies or MERS-CoV RBD-specific nanobodies did not cross-neutralize NeoCoV or PDF-2180, an ACE2-specific antibody and two broadly neutralizing betacoronavirus antibodies efficiently inhibited these two pseudotyped viruses. We describe MERS-CoV-related viruses that use ACE2 as an entry receptor, underscoring a promiscuity of receptor use and a potential zoonotic threat.

Date: 2022
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DOI: 10.1038/s41586-022-05513-3

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