The Rhinolophus affinis bat ACE2 and multiple animal orthologs are functional receptors for bat coronavirus RaTG13 and SARS-CoV-2

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Bat coronavirus (CoV) RaTG13 shares the highest genome sequence identity with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among all known coronaviruses, and also uses human angiotensin converting enzyme 2 (hACE2) for virus entry. Thus, SARS-CoV-2 is thought to have originated from bat. However, whether SARS-CoV-2 emerged from bats directly or through an intermediate host remains elusive. Here, we found that Rhinolophus affinis bat ACE2 (RaACE2) is an entry receptor for both SARS-CoV-2 and RaTG13, although the binding of RaACE2 to the receptor-binding domain (RBD) of SARS-CoV-2 is markedly weaker than that of hACE2. We further evaluated the receptor activities of ACE2s from additional 16 diverse animal species for RaTG13, SARS-CoV, and SARS-CoV-2 in terms of S protein binding, membrane fusion, and pseudovirus entry. We found that the RaTG13 spike (S) protein is significantly less fusogenic than SARS-CoV and SARS-CoV-2, and seven out of sixteen different ACE2s function as entry receptors for all three viruses, indicating that all three viruses might have broad host rages. Of note, RaTG13 S pseudovirions can use mouse, but not pangolin ACE2, for virus entry, whereas SARS-CoV-2 S pseudovirions can use pangolin, but not mouse, ACE2 enter cells efficiently. Mutagenesis analysis revealed that residues 484 and 498 in RaTG13 and SARS-CoV-2 S proteins play critical roles in recognition of mouse and human ACE2s. Finally, two polymorphous Rhinolophous sinicus bat ACE2s showed different susceptibilities to virus entry by RaTG13 and SARS-CoV-2 S pseudovirions, suggesting possible coevolution. Our results offer better understanding of the mechanism of coronavirus entry, host range, and virus-host coevolution.

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Electronic Article

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Science bulletin - Vol. 66, No. 12 (2021), p. 1215-1227




Li, Pei
Guo, Ruixuan
Liu, Yan
Zhang, Yingtao
Hu, Jiaxin
Ou, Xiuyuan
Mi, Dan
Chen, Ting
Mu, Zhixia
Han, Yelin
Chen, Zihan
Cui, Zhewei
Zhang, Leiliang
Wang, Xinquan
Wu, Zhiqiang
Wang, Jianwei
Jin, Qi
Qian, Zhaohui




Bat coronavirus RaTG13
Coronavirus entry
Host susceptibility
Journal Article
Rhinolophus affinis bat ACE2
Spike protein


Date Revised 04.06.2021

published: Print-Electronic

Citation Status PubMed-not-MEDLINE

Copyright: From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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