OmniVira

Broader-species receptor binding and structural bases of Omicron SARS-CoV-2 to both mouse and palm-civet ACE2s.

Linjie Li1,2 Pu Han1 Baihan Huang1 Yufeng Xie1,3 Weiwei Li1,2 Di Zhang1,4 Pengcheng Han1,5 Zepeng Xu1,4 Bin Bai1,2 Jingya Zhou1,2 Xinrui Kang1,2 Xiaomei Li6 Anqi Zheng1,2 Rong Zhang1,7 Shitong Qiao1,2 Xin Zhao1 Jianxun Qi1,2 Qihui Wang1,2 Kefang Liu8 George Fu Gao9,10
Affiliations 10 institutions
  1. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  2. University of Chinese Academy of Sciences, Beijing, China.
  3. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
  4. Faculty of Health Sciences, University of Macau, Macau, Macau SAR, China.
  5. School of Medicine, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China.
  6. Cryo-EM Center, Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China.
  7. State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi, China.
  8. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. [email protected].
  9. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. [email protected].
  10. University of Chinese Academy of Sciences, Beijing, China. [email protected].
PMID35821014 DOI10.1038/s41421-022-00431-0 Year2022 Journal Cell discovery Cell Discov Languageeng Statusepublish

Abstract

The Omicron variant of SARS-CoV-2 carries multiple unusual mutations, particularly in the receptor-binding domain (RBD) of the spike (S) protein. Moreover, host-adapting mutations, such as residues 493, 498, and 501, were also observed in the Omicron RBD, which indicates that it is necessary to evaluate the interspecies transmission risk of the Omicron variant. Herein, we evaluated the interspecies recognition of the Omicron BA.1 and Delta RBDs by 27 ACE2 orthologs, including humans. We found that Omicron BA.1 expanded its receptor binding spectra to palm-civet, rodents, more bats (least horseshoe bat and greater horseshoe bat) and lesser hedgehog tenrec. Additionally, we determined the cryo-electron microscopy (cryo-EM) structure of the Omicron BA.1 S protein complexed with mouse ACE2 (mACE2) and the crystal structure of Omicron RBD complexed with palm-civet ACE2 (cvACE2). Several key residues for the host range have been identified. These results suggest that surveillance should be enhanced on the Omicron variant for its broader-species receptor binding to prevent spillover and expansion of reservoir hosts for a prolonged pandemic.

Supporting text Virus Host Location

Evidence records

3 total
Functional Mechanism
3 records · 2 evidence types
Evidence type Receptor Usage
2 records
OVE6141 Receptor Usage
Key finding

Cryo-EM and crystal structures show Omicron BA.1 spike and RBD directly complexed with mouse and palm-civet ACE2, confirming receptor binding interactions.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system masked palm civet Paguma larvata Experimental system
Location
Not specified
Supporting text

We determined the cryo-electron microscopy (cryo-EM) structure of the Omicron BA.1 S protein complexed with mouse ACE2 (mACE2) and the crystal structure of Omicron RBD complexed with palm-civet ACE2 (cvACE2).

Method
cryo-electron microscopy | X-ray crystallography
Receptors
ACE2
OVE6140 Receptor Usage
Key finding

Omicron BA.1 spike RBD binds ACE2 receptors from multiple species, expanding receptor binding to palm-civet, rodents, least and greater horseshoe bats, and lesser hedgehog tenrec.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
masked palm civet Paguma larvata Experimental system rodents Rodentia Experimental system least horseshoe bat Rhinolophus pusillus Experimental system greater horseshoe bat Rhinolophus ferrumequinum Experimental system small Madagascar hedgehog Echinops telfairi Experimental system
Location
Not specified
Supporting text

We found that Omicron BA.1 expanded its receptor binding spectra to palm-civet, rodents, more bats (least horseshoe bat and greater horseshoe bat) and lesser hedgehog tenrec.

Method
receptor binding assay | ACE2 ortholog screening
Receptors
ACE2
Evidence type Molecular Adaptation
1 records
OVE6142 Molecular Adaptation
Key finding

Host-adapting mutations at residues 493, 498, and 501 in the Omicron SARS-CoV-2 RBD are linked to broader receptor binding and potential cross-species recognition.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

Host-adapting mutations, such as residues 493, 498, and 501, were also observed in the Omicron RBD, which indicates that it is necessary to evaluate the interspecies transmission risk of the Omicron variant.

Genes or proteins
RBD | Spike protein
Receptors
ACE2
Mutations
residue 493 | residue 498 | residue 501
Mechanism types
receptor binding | host-range expansion