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 Shirakawa, Akifumi Takaori-Kondo, Teresa Brevini, Donna L. Mallery, Oscar J. Charles, 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 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 () and Ravindra K. Gupta ()
Additional contact information
Bo Meng: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Adam Abdullahi: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Isabella A. T. M. Ferreira: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Niluka Goonawardane: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
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)
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)
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
Laurelle Jackson: Africa Health Research Institute
Darren Martin: University of Cape Town
Kenneth G. C. Smith: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
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
Kerstin B. Meyer: Welcome Sanger Institute, Wellcome Trust Genome Campus
Petra Mlcochova: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
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
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
Leo C. James: MRC—Laboratory of Molecular Biology
Lipi Thukral: CSIR Institute of Genomics and Integrative Biology
David Veesler: University of Washington
Alex Sigal: Africa Health Research Institute
Fotios Sampaziotis: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Ian G. Goodfellow: University of Cambridge
Nicholas J. Matheson: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Kei Sato: The University of Tokyo
Ravindra K. Gupta: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)

Nature, 2022, vol. 603, issue 7902, 706-714

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04474-x

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