SARS-CoV-2 Omicron Specific Mutations Affecting Infectivity, Fusogenicity, and Partial TMPRSS2-Independency

Area of Science:

• Virology
• Molecular Biology
• Genetics

Background:

• The COVID-19 pandemic is driven by SARS-CoV-2, with frequent emergence of variants of concern (VOCs).
• SARS-CoV-2 entry into host cells occurs via endocytosis or membrane fusion, influenced by TMPRSS2.
• The Omicron variant exhibits altered infectivity and cell-cell fusion (syncytia formation) compared to the Delta variant.

Purpose of the Study:

• To characterize the specific mutations in the Omicron variant and their impact on SARS-CoV-2 infectivity and cell entry.
• To investigate the phenotypic consequences of Omicron-specific residues and their reversion to Delta sequences.

Main Methods:

• Utilized SARS-CoV-2 pseudovirions to assess viral infectivity.
• Analyzed the role of specific Spike protein residues (F375, Y655) in viral entry and TMPRSS2 dependency.
• Introduced Omicron revertant mutations (Y655H, K764N, K856N, K969N) to evaluate their effect on cytopathic effects.

Main Results:

• Omicron Spike residue F375 significantly decreases infectivity; reversion to Delta S375 increases Omicron infectivity.
• Omicron residue Y655 reduces TMPRSS2 dependency and membrane fusion entry.
• Omicron revertant mutations (Y655H, K764N, K856N, K969N) enhance cell-cell fusion, indicating reduced viral severity.

Conclusions:

• Omicron-specific mutations, particularly at F375 and Y655, alter SARS-CoV-2 infectivity and cell entry mechanisms.
• These mutations may contribute to the reduced severity observed with the Omicron variant.
• Understanding the genotype-phenotype correlation of VOCs is crucial for monitoring and preparedness.