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Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.
Meng, Bo; Abdullahi, Adam; Ferreira, Isabella A T M; Goonawardane, Niluka; Saito, Akatsuki; Kimura, Izumi; Yamasoba, Daichi; Gerber, Pehuén Pereyra; Fatihi, Saman; Rathore, Surabhi; Zepeda, Samantha K; Papa, Guido; Kemp, Steven A; Ikeda, Terumasa; Toyoda, Mako; Tan, Toong Seng; Kuramochi, Jin; Mitsunaga, Shigeki; Ueno, Takamasa; Shirakawa, Kotaro; Takaori-Kondo, Akifumi; Brevini, Teresa; Mallery, Donna L; Charles, Oscar J; Bowen, John E; Joshi, Anshu; Walls, Alexandra C; Jackson, Laurelle; Martin, Darren; Smith, Kenneth G C; Bradley, John; Briggs, John A G; Choi, Jinwook; Madissoon, Elo; Meyer, Kerstin B; Mlcochova, Petra; Ceron-Gutierrez, Lourdes; Doffinger, Rainer; Teichmann, Sarah A; Fisher, Andrew J; Pizzuto, Matteo S; de Marco, Anna; Corti, Davide; Hosmillo, Myra; Lee, Joo Hyeon; James, Leo C; Thukral, Lipi; Veesler, David; Sigal, Alex; Sampaziotis, Fotios.
  • Meng B; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • Abdullahi A; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Ferreira IATM; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • Goonawardane N; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Saito A; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • Kimura I; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Yamasoba D; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • Gerber PP; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Fatihi S; Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
  • Rathore S; Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Zepeda SK; Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Papa G; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • Kemp SA; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Ikeda T; CSIR Institute of Genomics and Integrative Biology, Delhi, India.
  • Toyoda M; CSIR Institute of Genomics and Integrative Biology, Delhi, India.
  • Tan TS; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Kuramochi J; MRC-Laboratory of Molecular Biology, Cambridge, UK.
  • Mitsunaga S; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • Ueno T; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Shirakawa K; Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
  • Takaori-Kondo A; Division of Infection and Immunity, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
  • Brevini T; Division of Infection and Immunity, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
  • Mallery DL; Kuramochi Clinic Interpark, Utsunomiya, Japan.
  • Charles OJ; Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan.
  • Bowen JE; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Joshi A; MRC-Laboratory of Molecular Biology, Cambridge, UK.
  • Walls AC; Division of Infection and Immunity, UCL, London, UK.
  • Bradley J; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Briggs JAG; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Choi J; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Madissoon E; Department of Virology, University of Cambridge, Cambridge, UK.
  • Meyer KB; Africa Health Research Institute, Durban, South Africa.
  • Mlcochova P; University of Cape Town, Cape Town, South Africa.
  • Ceron-Gutierrez L; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • Doffinger R; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Teichmann SA; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Fisher AJ; Max Planck Institute of Biochemistry, Martinsried, Germany.
  • Pizzuto MS; Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • de Marco A; Welcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  • Corti D; European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, UK.
  • Hosmillo M; Welcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  • Lee JH; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.
  • James LC; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Thukral L; Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
  • Veesler D; Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
  • Sigal A; Welcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  • Sampaziotis F; Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK.
Nature ; 603(7902): 706-714, 2022 03.
Article in English | MEDLINE | ID: covidwho-1764186
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Serine Endopeptidases / Virus Internalization / SARS-CoV-2 / COVID-19 / Membrane Fusion Type of study: Experimental Studies Topics: Vaccines / Variants Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-022-04474-x

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Serine Endopeptidases / Virus Internalization / SARS-CoV-2 / COVID-19 / Membrane Fusion Type of study: Experimental Studies Topics: Vaccines / Variants Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-022-04474-x