Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity
Bo Meng(University of Cambridge), Adam Abdullahi(University of Cambridge), Isabella A.T.M. Ferreira(University of Cambridge), Niluka Goonawardane(University of Cambridge), Akatsuki Saito(University of Miyazaki), Izumi Kimura(National Institute of Infectious Diseases), Daichi Yamasoba(National Institute of Infectious Diseases), Pehuén Pereyra Gerber(University of Cambridge), Saman Fatihi(Institute of Genomics and Integrative Biology), Surabhi Rathore(Institute of Genomics and Integrative Biology), Samantha K. Zepeda(University of Washington), Guido Papa(MRC Laboratory of Molecular Biology), Steven A. Kemp(University of Cambridge), Terumasa Ikeda(Kumamoto University), Mako Toyoda(Kumamoto University), Toong Seng Tan(Kumamoto University), Jin Kuramochi(Saiseikai Utsunomiya hospital), Shigeki Mitsunaga(National Institute of Genetics), Takamasa Ueno(Kumamoto University), Kotaro Shirakawa(Kyoto University), Akifumi Takaori‐Kondo(Kyoto University), Teresa Brevini(University of Cambridge), Donna L. Mallery(MRC Laboratory of Molecular Biology), Oscar Charles(University College London), Stephen Baker, Gordon Dougan(University of Cambridge), Christoph Hess(University of Cambridge), Nathalie Kingston(Cambridge University Hospitals NHS Foundation Trust), Paul J. Lehner(University of Cambridge), Paul Lyons(University of Cambridge), Nicholas J. Matheson(NHS Blood and Transplant), Willem H. Ouwehand(University of Cambridge), Caroline Saunders(Cambridge University Hospitals NHS Foundation Trust), Charlotte Summers(University of Cambridge), James Thaventhiran(Cambridge University Hospitals NHS Foundation Trust), Mark Toshner(University of Cambridge), Michael P. Weekes(University of Cambridge), Patrick H. Maxwell(Cambridge University Hospitals NHS Foundation Trust), Ashley Shaw(Cambridge University Hospitals NHS Foundation Trust), Ashlea Bucke(Cambridge University Hospitals NHS Foundation Trust), Jo Calder(Cambridge University Hospitals NHS Foundation Trust), Laura Canna(Cambridge University Hospitals NHS Foundation Trust), Jason Domingo(Cambridge University Hospitals NHS Foundation Trust), Anne Elmer(Cambridge University Hospitals NHS Foundation Trust), Stewart Fuller(Cambridge University Hospitals NHS Foundation Trust), Julie Harris(Cambridge University Hospitals NHS Foundation Trust), Sarah Hewitt(Cambridge University Hospitals NHS Foundation Trust), Jane Kennet(Cambridge University Hospitals NHS Foundation Trust), Sherly Jose(Cambridge University Hospitals NHS Foundation Trust), Jenny Kourampa(Cambridge University Hospitals NHS Foundation Trust), Anne Meadows(Cambridge University Hospitals NHS Foundation Trust), Criona O’Brien(Cambridge University Hospitals NHS Foundation Trust), Jane Price(Cambridge University Hospitals NHS Foundation Trust), Cherry Publico(Cambridge University Hospitals NHS Foundation Trust), Rebecca Rastall(Cambridge University Hospitals NHS Foundation Trust), Carla M. S. Ribeiro(Cambridge University Hospitals NHS Foundation Trust), Jane Rowlands(Cambridge University Hospitals NHS Foundation Trust), Valentina Ruffolo(Cambridge University Hospitals NHS Foundation Trust), Hugo Tordesillas(Cambridge University Hospitals NHS Foundation Trust), Ben Bullman(University of Cambridge), Benjamin J. Dunmore(University of Cambridge), Stefan Ting Graf(University of Cambridge), Josh Hodgson(University of Cambridge), Christopher Huang(University of Cambridge), Kelvin Hunter(University of Cambridge), Emma Jones(Universidad San Francisco de Quito), Ekaterina Legchenko(University of Cambridge), Cecilia Matara(University of Cambridge), Jennifer Martin(University of Cambridge), Federica Mescia(University of Cambridge), Ciara O’Donnell(University of Cambridge), Linda Pointon(University of Cambridge), Joy Shih(University of Cambridge), Rachel Sutcliffe(University of Cambridge), Tobias Tilly(University of Cambridge), Carmen Treacy(University of Cambridge), Zhen Tong(University of Cambridge), Jennifer Wood(University of Cambridge), Marta Wylot(University of Cambridge), Ariana Betancourt(University of Cambridge), Georgie Bower(University of Cambridge), Chiara Cossetti(University of Cambridge), Aloka De(University of Cambridge), Madeline Epping(University of Cambridge), Stuart Fawke(University of Cambridge), Nick Gleadall(University of Cambridge), Richard Grenfell(University of Cambridge), Andrew Hinch(University of Cambridge), Sarah Jackson(University of Cambridge), Isobel Jarvis(Cambridge University Hospitals NHS Foundation Trust), Benjamin A. Krishna(University of Cambridge), Francesca Nice(Cambridge University Hospitals NHS Foundation Trust), Ommar Omarjee(University of Cambridge), Marianne Perera(University of Cambridge), Martin Potts(University of Cambridge), Nathan Richoz(University of Cambridge), Veronika Romashova(University of Cambridge), Luca Stefanucci(University of Cambridge), Mateusz Strezlecki(University of Cambridge), Lori Turner(University of Cambridge), Eckart M. D. D. De Bie(University of Cambridge), Katherine Bunclark(University of Cambridge), Maša Josipović(University of Cambridge), Michael Mackay(University of Cambridge), Helen Butcher(Cambridge University Hospitals NHS Foundation Trust), Daniela Caputo(Cambridge University Hospitals NHS Foundation Trust), Matt Chandler(Cambridge University Hospitals NHS Foundation Trust), Patrick F. Chinnery(Cambridge University Hospitals NHS Foundation Trust), Debbie Clapham-Riley(Cambridge University Hospitals NHS Foundation Trust), Eleanor Dewhurst(Cambridge University Hospitals NHS Foundation Trust), Christian Fernandez(Cambridge University Hospitals NHS Foundation Trust), Anita Furlong(Cambridge University Hospitals NHS Foundation Trust), Barbara Graves(Cambridge University Hospitals NHS Foundation Trust), Jennifer Gray(Cambridge University Hospitals NHS Foundation Trust), Sabine Hein(Cambridge University Hospitals NHS Foundation Trust), Tasmin Ivers(Cambridge University Hospitals NHS Foundation Trust), Emma Le Gresley(Cambridge University Hospitals NHS Foundation Trust), Rachel Linger(Cambridge University Hospitals NHS Foundation Trust), Mary Kasanicki(Cambridge University Hospitals NHS Foundation Trust), Rebecca L. King(Cambridge University Hospitals NHS Foundation Trust), Nathalie Kingston(Cambridge University Hospitals NHS Foundation Trust), Sarah Meloy(Cambridge University Hospitals NHS Foundation Trust), Alexei Moulton(Cambridge University Hospitals NHS Foundation Trust), Francesca Muldoon(Cambridge University Hospitals NHS Foundation Trust), Nigel Ovington(Cambridge University Hospitals NHS Foundation Trust), Sofia Papadia(Cambridge University Hospitals NHS Foundation Trust), Christopher J. Penkett(Cambridge University Hospitals NHS Foundation Trust), Isabel Phelan(Cambridge University Hospitals NHS Foundation Trust), Venkatesh-Prasad Ranganath(Cambridge University Hospitals NHS Foundation Trust), Roxana Paraschiv(Cambridge University Hospitals NHS Foundation Trust), Abigail Sage(Cambridge University Hospitals NHS Foundation Trust), Jennifer Sambrook(Cambridge University Hospitals NHS Foundation Trust), Ingrid Scholtes(Cambridge University Hospitals NHS Foundation Trust), Katherine Schon(Cambridge University Hospitals NHS Foundation Trust), Hannah Stark(Cambridge University Hospitals NHS Foundation Trust), Kathleen Stirrups(Cambridge University Hospitals NHS Foundation Trust), Paul Townsend(Cambridge University Hospitals NHS Foundation Trust), Neil Walker(Cambridge University Hospitals NHS Foundation Trust), Jennifer Webster(Cambridge University Hospitals NHS Foundation Trust), Erika P. Butlertanaka(University of Miyazaki), Yuri Tanaka(University of Miyazaki), Jumpei Ito(University of Miyazaki), Keiya Uriu(National Institute of Infectious Diseases), Yusuke Kosugi(National Institute of Infectious Diseases), Mai Suganami(National Institute of Infectious Diseases), Akiko Oide(National Institute of Infectious Diseases), Miyabishara Yokoyama(National Institute of Infectious Diseases), Mika Chiba(National Institute of Infectious Diseases), Chihiro Motozono(Kumamoto University), Hesham Nasser(Kumamoto University), Ryo Shimizu(Kumamoto University), Kazuko Kitazato(Kumamoto University), Haruyo Hasebe(Kumamoto University), Takashi Irie(Hiroshima University), So Nakagawa(Tokai University), Jiaqi Wu(Tokai University), Miyoko Takahashi(Tokai University), Takasuke Fukuhara(Hokkaido University), Kenta Shimizu(Hokkaido University), Kana Tsushima(Hokkaido University), Haruko Kubo(Hokkaido University), Yasuhiro Kazuma(Kyoto University), Ryosuke Nomura(Kyoto University), Yoshihito Horisawa(Kyoto University), Kayoko Nagata(Kyoto University), Yugo Kawai(Kyoto University), Yohei Yanagida(Kyoto University), Yusuke Tashiro(Kyoto University), Kenzo Tokunaga(National Institute of Infectious Diseases), Seiya Ozono(National Institute of Infectious Diseases), Ryoko Kawabata(Hiroshima University), Nanami Morizako(University of Miyazaki), Kenji Sadamasu(Tokyo Metropolitan Institute of Public Health), Hiroyuki Asakura(Tokyo Metropolitan Institute of Public Health), Mami Nagashima(Tokyo Metropolitan Institute of Public Health), Kazuhisa Yoshimura(Tokyo Metropolitan Institute of Public Health), Paúl Cárdenas(Universidad San Francisco de Quito), Érika Muñoz(Universidad San Francisco de Quito), Verónica Barragán(Universidad San Francisco de Quito), Sully Márquez(Universidad San Francisco de Quito), Belén Prado-Vivar(Universidad San Francisco de Quito), Mónica Becerra-Wong(Universidad San Francisco de Quito), Mateo Caravajal(Universidad San Francisco de Quito), Gabriel Trueba(Universidad San Francisco de Quito), Patricio Rojas‐Silva(Universidad San Francisco de Quito), Michelle Grunauer(Universidad San Francisco de Quito), Bernardo Gutiérrez(Universidad San Francisco de Quito), Juan José Guadalupe(Universidad San Francisco de Quito), Juan Carlos Fernández‐Cadena(University of Guayaquil), Derly Andrade-Molina(University of Guayaquil), Manuel E. Baldeón(Universidad Internacional del Ecuador), Andrea Pinos(Universidad de Las Américas), John E. Bowen(University of Washington), Anshu Joshi(University of Washington), Alexandra C. Walls(University of Washington), Laurelle Jackson(Africa Health Research Institute), Darren P. Martin(University of Cape Town), Kenneth G. C. Smith(University of Cambridge), John R. Bradley(University of Cambridge), John A. G. Briggs(Max Planck Institute of Biochemistry), Jinwook Choi(Wellcome/MRC Cambridge Stem Cell Institute), Elo Madissoon(European Bioinformatics Institute), Kerstin B. Meyer(Wellcome Sanger Institute), Petra Mlčochová(University of Cambridge), Lourdes Ceron‐Gutierrez(Cambridge University Hospitals NHS Foundation Trust), Rainer Döffinger(Cambridge University Hospitals NHS Foundation Trust), Sarah A. Teichmann(University of Cambridge), Andrew J. Fisher(Newcastle University), Matteo Samuele Pizzuto(Vir Biotechnology (Switzerland)), Anna De Marco(Vir Biotechnology (Switzerland)), Davide Corti(Vir Biotechnology (Switzerland)), Myra Hosmillo(University of Cambridge), Joo Hyeon Lee(Wellcome/MRC Cambridge Stem Cell Institute), Leo C. James(MRC Laboratory of Molecular Biology), Lipi Thukral(Institute of Genomics and Integrative Biology), David Veesler(Howard Hughes Medical Institute), Alex Sigal(Max Planck Institute for Infection Biology), Fotios Sampaziotis(Wellcome/MRC Cambridge Stem Cell Institute), Ian Goodfellow(University of Cambridge), Nicholas J. Matheson(NHS Blood and Transplant), Kei Sato(National Institute of Infectious Diseases), Ravindra K. Gupta(University of Cambridge)
Cited by 1,163Open Access
Abstract
Abstract The SARS-CoV-2 Omicron BA.1 variant emerged in 2021 1 and has multiple mutations in its spike protein 2 . 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 pathways 3 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.
Related Papers
No related papers found
Powered by citation graph analysis