Portal de Periódicos da CAPES

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

2022; Nature Portfolio; Volume: 603; Issue: 7902 Linguagem: Inglês

10.1038/s41586-022-04474-x

1476-4687

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 Charles, Stephen Baker, Gordon Dougan, Christoph Hess, Nathalie Kingston, Paul J. Lehner, Paul Lyons, Nicholas J. Matheson, Willem H. Ouwehand, Caroline Saunders, Charlotte Summers, James Thaventhiran, Mark Toshner, Michael P. Weekes, Patrick H. Maxwell, Ashley Shaw, Ashlea Bucke, Jo Calder, Laura Canna, Jason Domingo, Anne Elmer, Stewart Fuller, Julie Harris, Sarah Hewitt, Jane Kennet, Sherly Jose, Jenny Kourampa, Anne Meadows, Criona O’Brien, Jane Price, Cherry Publico, Rebecca Rastall, Carla M. S. Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Ben Bullman, Benjamin J. Dunmore, Stefan Ting Graf, Josh Hodgson, Christopher Huang, Kelvin Hunter, Emma Jones, Ekaterina Legchenko, Cecilia Matara, Jennifer Martin, Federica Mescia, Ciara O’Donnell, Linda Pointon, Joy Shih, Rachel Sutcliffe, Tobias Tilly, Carmen Treacy, Zhen Tong, Jennifer Wood, Marta Wylot, Ariana Betancourt, Georgie Bower, Chiara Cossetti, Aloka De, Madeline Epping, Stuart Fawke, Nick Gleadall, Richard Grenfell, Andrew Hinch, Sarah Jackson, Isobel Jarvis, Benjamin A. Krishna, Francesca Nice, Ommar Omarjee, Marianne Perera, Martin Potts, Nathan Richoz, Veronika Romashova, Luca Stefanucci, Mateusz Strezlecki, Lori Turner, Eckart M. D. D. De Bie, Katherine Bunclark, Maša Josipović, Michael Mackay, Helen Butcher, Daniela Caputo, Matt Chandler, Patrick F. Chinnery, Debbie Clapham-Riley, Eleanor Dewhurst, Christian Fernandez, Anita Furlong, Barbara Graves, Jennifer Gray, Sabine Hein, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Mary Kasanicki, Rebecca L. King, Nathalie Kingston, Sarah Meloy, Alexei Moulton, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Christopher J. Penkett, Isabel Phelan, Venkatesh-Prasad Ranganath, Roxana Paraschiv, Abigail Sage, Jennifer Sambrook, Ingrid Scholtes, Katherine Schon, Hannah Stark, Kathleen Stirrups, Paul Townsend, Neil Walker, Jennifer Webster, Erika P. Butlertanaka, Yuri Tanaka, Jumpei Ito, Keiya Uriu, Yusuke Kosugi, Mai Suganami, Akiko Oide, Miyabishara Yokoyama, Mika Chiba, Chihiro Motozono, Hesham Nasser, Ryo Shimizu, Kazuko Kitazato, Haruyo Hasebe, Takashi Irie, So Nakagawa, Jiaqi Wu, Miyoko Takahashi, Takasuke Fukuhara, Kenta Shimizu, Kana Tsushima, Haruko Kubo, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Kayoko Nagata, Yugo Kawai, Yohei Yanagida, Yusuke Tashiro, Kenzo Tokunaga, Seiya Ozono, Ryoko Kawabata, Nanami Morizako, Kenji Sadamasu, Hiroyuki Asakura, Mami Nagashima, Kazuhisa Yoshimura, Paúl Cárdenas, Érika Muñoz, Verónica Barragán, Sully Márquez, Belén Prado-Vivar, Mónica Becerra-Wong, Mateo Caravajal, Gabriel Trueba, Patricio Rojas‐Silva, Michelle Grunauer, Bernardo Gutiérrez, Juan José Guadalupe, Juan Carlos Fernández‐Cadena, Derly Andrade-Molina, Manuel E. Baldeón, Andrea Pinos, John E. Bowen, Anshu Joshi, Alexandra C. Walls, Laurelle Jackson, Darren P. Martin, Kenneth G. C. Smith, John R. Bradley, John A. G. Briggs, Jinwook Choi, Elo Madissoon, Kerstin B. Meyer, Petra Mlčochová, Lourdes Ceron‐Gutierrez, Rainer Döffinger, Sarah A. Teichmann, Andrew J. Fisher, Matteo Samuele Pizzuto, Anna De Marco, Davide Corti, Myra Hosmillo, Joo‐Hyeon Lee, Leo C. James, Lipi Thukral, David Veesler, Alex Sigal, Fotios Sampaziotis, Ian Goodfellow, Nicholas J. Matheson, Kei Sato, Ravindra K. Gupta,

Respiratory viral infections research

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.