OmniVira

Spike protein-independent attenuation of SARS-CoV-2 Omicron variant in laboratory mice.

Shufeng Liu1 Prabhuanand Selvaraj1 Kotou Sangare1 Binquan Luan2 Tony T Wang3
Affiliations 3 institutions
  1. Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
  2. Computational Biological Center, IBM Thomas J. Watson Research, Yorktown Heights, NY 10598, USA. Electronic address: [email protected].
  3. Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: [email protected].
PMID36075211 DOI10.1016/j.celrep.2022.111359 Year2022 Journal Cell reports Cell Rep Languageeng Statusppublish

Abstract

Despite being more transmissible, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant only causes milder diseases in laboratory animals, often accompanied by a lower viral load compared with previous variants of concern. In this study, we report the structural basis for a robust interaction between the receptor-binding domain of the Omicron spike protein and mouse ACE2. We show that pseudovirus bearing the Omicron spike protein efficiently utilizes mouse ACE2 for entry. By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron spike or only the N501Y/Q493R mutations in its spike, we find that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load. Together, our results imply that a post-entry block to the Omicron variant exists in laboratory mice.

Supporting text Virus Host Location
attenuation 2 Balb/c mice 2 CP: Microbiology 7 K18-hACE2 2 Omicron variant 7 SARS-CoV-2 550 Angiotensin-Converting Enzyme 2 177 COVID-19 425 Animals 1948 Mice 253 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 Virus Internalization 100 SARS-CoV-2 variants 86 spike protein, SARS-CoV-2 157

Evidence records

3 total
Experimental Infection
1 records · 1 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE6346 Pathogenicity Experiment
Key finding

Laboratory mice experimentally infected with the SARS-CoV-2 Omicron variant showed milder disease and lower viral load compared with infections by previous variants of concern.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

Despite being more transmissible, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant only causes milder diseases in laboratory animals, often accompanied by a lower viral load compared with previous variants of concern.

Method
experimental infection | viral load comparison | assessment of disease severity
Experimental system
in vivo laboratory mouse infection model
Functional Mechanism
2 records · 2 evidence types
Evidence type Receptor Usage
1 records
OVE6345 Receptor Usage
Key finding

The SARS-CoV-2 Omicron variant spike protein receptor-binding domain interacts robustly with mouse ACE2, and Omicron pseudovirus efficiently uses mouse ACE2 for cell entry.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

We report the structural basis for a robust interaction between the receptor-binding domain of the Omicron spike protein and mouse ACE2. We show that pseudovirus bearing the Omicron spike protein efficiently utilizes mouse ACE2 for entry.

Method
structural analysis | pseudovirus entry assay
Receptors
mouse ACE2
Evidence type Molecular Adaptation
1 records
OVE6347 Molecular Adaptation
Key finding

Mutations located outside the spike protein in the SARS-CoV-2 Omicron variant are linked to reduced replication and post-entry attenuation in laboratory mice compared with recombinant viruses bearing the Omicron spike or N501Y/Q493R spike mutations.

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

By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron spike or only the N501Y/Q493R mutations in its spike, we find that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load.

Genes or proteins
spike protein
Mutations
N501Y | Q493R
Mechanism types
replication adaptation | virulence adaptation