SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells

Emerg Microbes Infect. 2022 Dec;11(1):277-283. doi: 10.1080/22221751.2021.2023329.

Abstract

The novel SARS-CoV-2 Omicron variant (B.1.1.529), first found in early November 2021, has sparked considerable global concern and it has >50 mutations, many of which are known to affect transmissibility or cause immune escape. In this study, we sought to investigate the virological characteristics of the Omicron variant and compared it with the Delta variant which has dominated the world since mid-2021. Omicron variant replicated more slowly than the Delta variant in transmembrane serine protease 2 (TMPRSS2)-overexpressing VeroE6 (VeroE6/TMPRSS2) cells. Notably, the Delta variant replicated well in Calu3 cell line which has robust TMPRSS2 expression, while the Omicron variant replicated poorly in this cell line. Competition assay showed that Delta variant outcompeted Omicron variant in VeroE6/TMPRSS2 and Calu3 cells. To confirm the difference in entry pathway between the Omicron and Delta variants, we assessed the antiviral effect of bafilomycin A1, chloroquine (inhibiting endocytic pathway), and camostat (inhibiting TMPRSS2 pathway). Camostat potently inhibited the Delta variant but not the Omicron variant, while bafilomycin A1 and chloroquine could inhibit both Omicron and Delta variants. Moreover, the Omicron variant also showed weaker cell-cell fusion activity when compared with Delta variant in VeroE6/TMPRSS2 cells. Collectively, our results suggest that Omicron variant infection is not enhanced by TMPRSS2 but is largely mediated via the endocytic pathway. The difference in entry pathway between Omicron and Delta variants may have an implication on the clinical manifestations or disease severity.

Keywords: Delta variant; Omicron variant; SARS-CoV-2; TMPRSS2; viral replication.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • COVID-19 / virology*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Chloroquine / pharmacology
  • Endocytosis / drug effects
  • Esters / pharmacology
  • Guanidines / pharmacology
  • Humans
  • Immune Evasion
  • Lung Neoplasms / pathology
  • Macrolides / pharmacology
  • Recombinant Proteins / metabolism
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / physiology*
  • Serine Endopeptidases / metabolism*
  • Vero Cells
  • Virus Cultivation
  • Virus Internalization* / drug effects
  • Virus Replication*
  • Whole Genome Sequencing

Substances

  • Esters
  • Guanidines
  • Macrolides
  • Recombinant Proteins
  • camostat
  • Chloroquine
  • bafilomycin A1
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

This study was partly supported by funding from the Theme-based Research Scheme (project no. T11-709/21-N) of the University Grant Committee, Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (COVID1903010-Project 13), and donations of Richard Yu and Carol Yu, Shaw Foundation Hong Kong, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Lee Wan Keung Charity Foundation Limited, Hong Kong Sanatorium & Hospital, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie & George Ho Charitable Foundation, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation Limited, Betty Hing-Chu Lee, and Ping Cham So.