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Nature
. 2022 Dec 7.
doi: 10.1038/s41586-022-05513-3. Online ahead of print.
Close relatives of MERS-CoV in bats use ACE2 as their functional receptors
Qing Xiong # 1 , Lei Cao # 2 , Chengbao Ma # 1 , M Alejandra Tortorici # 3 , Chen Liu 1 , Junyu Si 1 , Peng Liu 1 , Mengxue Gu 1 , Alexandra C Walls 3 4 , Chunli Wang 1 , Lulu Shi 1 , Fei Tong 1 , Meiling Huang 1 , Jing Li 1 , Chufeng Zhao 1 , Chao Shen 1 , Yu Chen 1 , Huabin Zhao 5 , Ke Lan 1 , Davide Corti 6 , David Veesler 7 8 , Xiangxi Wang 9 10 , Huan Yan 11
Affiliations
- PMID: 36477529
- DOI: 10.1038/s41586-022-05513-3
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.