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

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant exhibits increased transmissibility but causes milder disease in animal models.
• Previous variants of concern often led to higher viral loads and more severe illness in laboratory animals.

Purpose of the Study:

• To investigate the structural basis for the Omicron variant's interaction with mouse ACE2.
• To determine the factors contributing to the reduced viral load and milder disease observed with the Omicron variant in mice.

Main Methods:

• Structural analysis of the Omicron spike protein's receptor-binding domain (RBD) interaction with mouse ACE2.
• Pseudovirus entry assays using the Omicron spike protein and mouse ACE2.
• Comparative analysis of viral load and disease severity in mice infected with natural Omicron or recombinant viruses carrying specific Omicron spike mutations.

Main Results:

• The Omicron spike protein's RBD robustly interacts with mouse ACE2, facilitating efficient viral entry.
• Pseudoviruses with the Omicron spike efficiently utilize mouse ACE2.
• Mutations outside the Omicron spike protein, not within it, appear responsible for the reduced viral load in mice.

Conclusions:

• A post-entry restriction mechanism likely limits Omicron variant replication in laboratory mice.
• Understanding these post-entry barriers is crucial for developing effective antiviral strategies against SARS-CoV-2 variants.