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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
1CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
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.
Insights
The Omicron variant of SARS-CoV-2 shows expanded receptor binding to diverse species, including civets, rodents, bats, and tenrecs. Enhanced surveillance is crucial to prevent further spillover and host expansion, aiding pandemic control.
Area of Science:
- Virology
- Structural Biology
- Epidemiology
Background:
- The Omicron variant of SARS-CoV-2 possesses numerous mutations in its spike (S) protein's receptor-binding domain (RBD).
- Host-adapting mutations in the Omicron RBD suggest a need to assess interspecies transmission risks.
Purpose of the Study:
- To evaluate the interspecies receptor recognition of Omicron BA.1 and Delta RBDs using 27 ACE2 orthologs.
- To determine the structural basis for Omicron's altered host tropism.
Main Methods:
- Assessed binding of Omicron BA.1 and Delta RBDs to 27 ACE2 orthologs from various species.
- Determined cryo-electron microscopy (cryo-EM) structure of Omicron BA.1 S protein with mouse ACE2 (mACE2).
- Determined crystal structure of Omicron RBD with palm-civet ACE2 (cvACE2).
Main Results:
- Omicron BA.1 demonstrated broadened receptor binding to palm civet, rodents, certain bats (least horseshoe and greater horseshoe), and lesser hedgehog tenrec.
- Identified key residues influencing the host range of the Omicron variant.
- Structural analysis revealed specific interactions mediating mACE2 and cvACE2 binding.
Conclusions:
- The Omicron variant exhibits an expanded host tropism compared to previous SARS-CoV-2 variants.
- Enhanced surveillance of the Omicron variant is recommended to mitigate spillover risks and prevent the establishment of new animal reservoirs.
- Understanding structural determinants of host binding is critical for predicting and controlling viral transmission.
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