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Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2

Bingjie Hu1, Jasper Fuk-Woo Chan1,2,3,4,5,6, Huan Liu1

  • 1State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China.

Emerging Microbes & Infections
|August 30, 2022
PubMed

Insights

Key mutations in the Omicron BA.1 and BA.2 spike proteins explain altered SARS-CoV-2 entry mechanisms. Understanding these viral determinants is crucial for assessing Omicron

Area of Science:

  • Virology
  • Molecular Biology
  • Infectious Diseases

Background:

  • The SARS-CoV-2 Omicron BA.1 variant rapidly became globally dominant due to significant spike protein mutations.
  • Omicron BA.1 exhibits altered virological characteristics, including reduced dependence on TMPRSS2, less efficient spike cleavage, and modified entry pathways compared to ancestral SARS-CoV-2.
  • Previous studies indicated these altered features are partly conserved in subsequent Omicron sublineages, but the specific spike determinants remain unclear.

Purpose of the Study:

  • To identify the specific mutations within the Omicron BA.1 and BA.2 spike proteins responsible for their altered virological properties.
  • To elucidate the molecular mechanisms underlying changes in viral entry and pathogenicity associated with Omicron sublineages.

Main Methods:

  • Comparative analysis of individual spike protein mutations in Omicron BA.1 and BA.2 variants.
  • Functional screening of specific mutations (e.g., 69-70 deletion, E484A, H655Y, 25-27 deletion, S375F, T376A) to assess their impact on TMPRSS2 usage, spike cleavage, and fusogenicity.
  • Evaluation of the effect of the H655Y substitution on viral entry pathways (plasma membrane vs. endosomal).

Main Results:

  • Specific mutations, including 69-70 deletion, E484A, and H655Y, were linked to reduced TMPRSS2 dependence.
  • Mutations 25-27 deletion, S375F, and T376A were associated with less efficient spike cleavage.
  • Shared mutations S375F and H655Y in BA.1 and BA.2 reduced spike-mediated fusogenicity.
  • The H655Y substitution was consistently found to decrease serine protease usage and increase endosomal protease utilization, facilitating endosomal entry.

Conclusions:

  • Key mutations in the Omicron spike protein, such as 69-70 deletion, E484A, H655Y, 25-27 deletion, S375F, and T376A, drive the altered virological characteristics of Omicron variants.
  • The H655Y mutation alone significantly impacts viral entry, favoring endosomal pathways over plasma membrane entry.
  • This study provides critical insights into the molecular determinants of Omicron's virology and pathogenicity, aiding in understanding its evolution and spread.
Keywords:
Omicron BA.1 and BA.2SARS-CoV-2endosomal entry pathwayentryfusogenicitypathogenesisspike protein cleavage

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