Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

Bo Meng, Adam Abdullahi, Isabella A.T.M. Ferreira, Niluka Goonawardane, Akatsuki Saito, Izumi Kimura, Daichi Yamasoba, Pehuén Pereyra Gerber, Saman Fatihi, Surabhi Rathore, Samantha K. Zepeda, Guido Papa, Steven A. Kemp, Terumasa Ikeda, Mako Toyoda, Toong Seng Tan, Jin Kuramochi, Shigeki Mitsunaga, Takamasa Ueno, Kotaro ShirakawaAkifumi Takaori-Kondo, Teresa Brevini, Donna L. Mallery, Oscar J. Charles, The CITIID-NIHR BioResource COVID-19 Collaboration, Julie Harris, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ecuador-COVID19 Consortium, John E. Bowen, Anshu Joshi, Alexandra C. Walls, Laurelle Jackson, Darren Martin, Kenneth G.C. Smith, John Bradley, John A.G. Briggs, Jinwook Choi, Elo Madissoon, Kerstin B. Meyer, Petra Mlcochova, Lourdes Ceron-Gutierrez, Rainer Doffinger, Sarah A. Teichmann, Andrew J. Fisher, Matteo S. Pizzuto, Anna de Marco, Davide Corti, Myra Hosmillo, Joo Hyeon Lee, Leo C. James, Lipi Thukral, David Veesler, Alex Sigal, Fotios Sampaziotis, Ian G. Goodfellow, Nicholas J. Matheson, Kei Sato, Ravindra K. Gupta

Research output: Contribution to journalArticlepeer-review

178 Citations (Scopus)

Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.

Original languageEnglish
Pages (from-to)706-714
Number of pages30
JournalNature
Volume603
DOIs
Publication statusPublished - 24 Mar 2022
Externally publishedYes

Keywords

  • COVID-19
  • Immune evasion
  • Omicron BA.1 variant
  • SARS-CoV-2

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