Literature detail

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

Pei Li¹ Ruixuan Guo¹ Yan Liu¹ Yingtao Zhang² Jiaxin Hu¹ Xiuyuan Ou¹ Dan Mi¹ Ting Chen¹ Zhixia Mu¹ Yelin Han¹ Zihan Chen¹ Zhewei Cui¹ Leiliang Zhang³ Xinquan Wang⁴ Zhiqiang Wu¹ Jianwei Wang¹ Qi Jin¹ Zhaohui Qian¹

Affiliations 4 institutions

NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100176, China.
School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250062, China.
The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing 100084, China.

PMID 33495713 2021 Sci Bull (Beijing) eng ppublish

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Article

Publication summary

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.

Bat coronavirus RaTG13 Coronavirus entry Host susceptibility Rhinolophus affinis bat ACE2 SARS-CoV-2 Spike protein

Structured evidence records

Evidence records

10 total

Host Range Experiment 4 records

Host Range Experiment Extraction confidence 0.95

Key finding

RaTG13 and SARS-CoV-2 can enter cells expressing Rhinolophus affinis bat ACE2, demonstrating functional receptor usage and differential binding affinity compared to human ACE2.

Virus

Host

Location

Supporting text

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.

Method: S protein binding; pseudovirus entry assay
Experimental system: pseudovirus assay

Host Range Experiment Extraction confidence 0.95

Key finding

RaTG13 spike mediates entry via mouse ACE2 but not pangolin ACE2, while SARS-CoV-2 spike mediates entry via pangolin ACE2 but not mouse ACE2.

Virus

Host

Location

Supporting text

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.

Method: pseudovirus entry assay
Experimental system: pseudovirus assay

Host Range Experiment Extraction confidence 0.95

Key finding

SARS-CoV-2 spike mediates efficient pseudovirus entry using pangolin ACE2 but not mouse ACE2, indicating host-specific receptor compatibility.

Virus

Host

Location

Supporting text

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.

Method: pseudovirus entry assay
Experimental system: pseudovirus assay

Host Range Experiment Extraction confidence 0.95

Key finding

Different ACE2 polymorphs from Rhinolophus sinicus bats displayed variable susceptibility to pseudovirus entry by RaTG13 and SARS-CoV-2, indicating receptor-dependent host range variation.

Virus

Host

Location

Supporting text

Two polymorphous Rhinolophous sinicus bat ACE2s showed different susceptibilities to virus entry by RaTG13 and SARS-CoV-2 S pseudovirions, suggesting possible coevolution.

Method: pseudovirus entry assay
Experimental system: pseudovirus assay

Receptor Usage 4 records

Receptor Usage Extraction confidence 1.00

Key finding

Rhinolophus affinis bat ACE2 mediates entry of both SARS-CoV-2 and RaTG13, showing weaker binding to the SARS-CoV-2 RBD than human ACE2.

Virus

Host

Location

Supporting text

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.

Method: binding assay; pseudovirus entry assay
Receptors: ACE2

Receptor Usage Extraction confidence 1.00

Key finding

RaTG13 spike uses mouse ACE2 but not pangolin ACE2 for entry, whereas SARS-CoV-2 spike uses pangolin ACE2 but not mouse ACE2.

Virus

Host

Location

Supporting text

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.

Method: pseudovirus entry assay
Receptors: ACE2

Receptor Usage Extraction confidence 1.00

Key finding

SARS-CoV-2 spike uses pangolin ACE2 but not mouse ACE2 to mediate cell entry.

Virus

Host

Location

Supporting text

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.

Method: pseudovirus entry assay
Receptors: ACE2

Receptor Usage Extraction confidence 1.00

Key finding

Residues 484 and 498 in the RaTG13 and SARS-CoV-2 spike proteins are key determinants for recognition of mouse and human ACE2 receptors.

Virus

Host

Location

Supporting text

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.

Method: mutagenesis analysis
Receptors: ACE2

Molecular Adaptation 2 records

Molecular Adaptation Extraction confidence 0.90

Key finding

Residues 484 and 498 in the spike proteins of RaTG13 and SARS-CoV-2 determine differential recognition of mouse and human ACE2 receptors, indicating adaptive changes influencing host range.

Virus

Host

Location

Supporting text

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.

Genes or proteins: spike
Receptors: ACE2
Mutations: residue 484; residue 498
Mechanism types: receptor_binding; host_range_adaptation

Molecular Adaptation Extraction confidence 0.90

Key finding

Residues 484 and 498 in the spike protein of bat coronavirus RaTG13 are critical for recognition of mouse ACE2, reflecting molecular adaptation to specific host receptors.

Virus

Host

Location

Supporting text

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.

Genes or proteins: spike
Receptors: ACE2
Mutations: residue 484; residue 498
Mechanism types: receptor_binding; host_range_adaptation

Citation context

References

43 references

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Evidence overview

Evidence 10

Types 3

Virus 2

Host 8

Evidence types

Host Range Experiment 4 Receptor Usage 4 Molecular Adaptation 2

Linked entities

Viruses

Hosts

Locations

Publication metadata

Journal: Science bulletin
Volume / Issue / Pages: 66 / 12 / 1215-1227
ISSN: 2095-9273
Journal country: Netherlands
DOI: 10.1016/j.scib.2021.01.011

The <i>Rhinolophus affinis</i> bat ACE2 and multiple animal orthologs are functional receptors for bat coronavirus RaTG13 and SARS-CoV-2.

Publication summary

Evidence records

References

Reference network