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

Author

Listed:
  • Bo Meng

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Adam Abdullahi

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Isabella A. T. M. Ferreira

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Niluka Goonawardane

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Akatsuki Saito

    (University of Miyazaki)

  • Izumi Kimura

    (The University of Tokyo)

  • Daichi Yamasoba

    (The University of Tokyo)

  • Pehuén Pereyra Gerber

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Saman Fatihi

    (CSIR Institute of Genomics and Integrative Biology)

  • Surabhi Rathore

    (CSIR Institute of Genomics and Integrative Biology)

  • Samantha K. Zepeda

    (University of Washington)

  • Guido Papa

    (MRC—Laboratory of Molecular Biology)

  • Steven A. Kemp

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Terumasa Ikeda

    (Kumamoto University)

  • Mako Toyoda

    (Kumamoto University)

  • Toong Seng Tan

    (Kumamoto University)

  • Jin Kuramochi

    (Kuramochi Clinic Interpark)

  • Shigeki Mitsunaga

    (Human Genetics Laboratory, National Institute of Genetics)

  • Takamasa Ueno

    (Kumamoto University)

  • Kotaro Shirakawa

    (Graduate School of Medicine, Kyoto University)

  • Akifumi Takaori-Kondo

    (Graduate School of Medicine, Kyoto University)

  • Teresa Brevini

    (University of Cambridge)

  • Donna L. Mallery

    (MRC—Laboratory of Molecular Biology)

  • Oscar J. Charles

    (UCL)

  • John E. Bowen

    (University of Washington)

  • Anshu Joshi

    (University of Washington)

  • Alexandra C. Walls

    (University of Washington
    University of Cambridge)

  • Laurelle Jackson

    (Africa Health Research Institute)

  • Darren Martin

    (University of Cape Town)

  • Kenneth G. C. Smith

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • John Bradley

    (University of Cambridge)

  • John A. G. Briggs

    (Max Planck Institute of Biochemistry)

  • Jinwook Choi

    (Wellcome-MRC Cambridge Stem Cell Institute)

  • Elo Madissoon

    (Welcome Sanger Institute, Wellcome Trust Genome Campus
    European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus)

  • Kerstin B. Meyer

    (Welcome Sanger Institute, Wellcome Trust Genome Campus)

  • Petra Mlcochova

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Lourdes Ceron-Gutierrez

    (Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus)

  • Rainer Doffinger

    (Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus)

  • Sarah A. Teichmann

    (Welcome Sanger Institute, Wellcome Trust Genome Campus
    University of Cambridge)

  • Andrew J. Fisher

    (Newcastle University)

  • Matteo S. Pizzuto

    (Humabs Biomed SA, a subsidiary of Vir Biotechnology)

  • Anna Marco

    (Humabs Biomed SA, a subsidiary of Vir Biotechnology)

  • Davide Corti

    (Humabs Biomed SA, a subsidiary of Vir Biotechnology)

  • Myra Hosmillo

    (University of Cambridge)

  • Joo Hyeon Lee

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge)

  • Leo C. James

    (MRC—Laboratory of Molecular Biology)

  • Lipi Thukral

    (CSIR Institute of Genomics and Integrative Biology)

  • David Veesler

    (University of Washington
    Howard Hughes Medical Institute)

  • Alex Sigal

    (Africa Health Research Institute
    Max Planck Institute for Infection Biology
    School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal)

  • Fotios Sampaziotis

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge
    Wellcome-MRC Cambridge Stem Cell Institute
    Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus)

  • Ian G. Goodfellow

    (University of Cambridge)

  • Nicholas J. Matheson

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge
    Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus
    NHS Blood and Transplant)

  • Kei Sato

    (The University of Tokyo
    CREST, Japan Science and Technology Agency)

  • Ravindra K. Gupta

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge
    Africa Health Research Institute)

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.

Suggested Citation

  • 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. Zep, 2022. "Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity," Nature, Nature, vol. 603(7902), pages 706-714, March.
  • Handle: RePEc:nat:nature:v:603:y:2022:i:7902:d:10.1038_s41586-022-04474-x
    DOI: 10.1038/s41586-022-04474-x
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