Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity
Authors: 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. ,   The CITIID-NIHR BioResource COVID-19 Collaboration, Baker Stephen , Dougan Gordon , Hess Christoph , Kingston Nathalie , Lehner Paul J. , Lyons Paul A. , Matheson Nicholas J. , Ouwehand Willem H. , Saunders Caroline , Summers Charlotte , Thaventhiran James E. D. , Toshner Mark , Weekes Michael P. , Maxwell Patrick , Shaw Ashley , Bucke Ashlea , Calder Jo , Canna Laura , Domingo Jason , Elmer Anne , Fuller Stewart , Harris Julie , Hewitt Sarah , Kennet Jane , Jose Sherly , Kourampa Jenny , Meadows Anne , O’Brien Criona , Price Jane , Publico Cherry , Rastall Rebecca , Ribeiro Carla , Rowlands Jane , Ruffolo Valentina , Tordesillas Hugo , Bullman Ben , Dunmore Benjamin J. , Gräf Stefan , Hodgson Josh , Huang Christopher , Hunter Kelvin , Jones Emma , Legchenko Ekaterina , Matara Cecilia , Martin Jennifer , Mescia Federica , O’Donnell Ciara , Pointon Linda , Shih Joy , Sutcliffe Rachel , Tilly Tobias , Treacy Carmen , Tong Zhen , Wood Jennifer , Wylot Marta , Betancourt Ariana , Bower Georgie , Cossetti Chiara , De Sa Aloka , Epping Madeline , Fawke Stuart , Gleadall Nick , Grenfell Richard , Hinch Andrew , Jackson Sarah , Jarvis Isobel , Krishna Ben , Nice Francesca , Omarjee Ommar , Perera Marianne , Potts Martin , Richoz Nathan , Romashova Veronika , Stefanucci Luca , Strezlecki Mateusz , Turner Lori , De Bie Eckart M. D. D. , Bunclark Katherine , Josipovic Masa , Mackay Michael , Butcher Helen , Caputo Daniela , Chandler Matt , Chinnery Patrick , Clapham-Riley Debbie , Dewhurst Eleanor , Fernandez Christian , Furlong Anita , Graves Barbara , Gray Jennifer , Hein Sabine , Ivers Tasmin , Le Gresley Emma , Linger Rachel , Kasanicki Mary , King Rebecca , Kingston Nathalie , Meloy Sarah , Moulton Alexei , Muldoon Francesca , Ovington Nigel , Papadia Sofia , Penkett Christopher J. , Phelan Isabel , Ranganath Venkatesh , Paraschiv Roxana , Sage Abigail , Sambrook Jennifer , Scholtes Ingrid , Schon Katherine , Stark Hannah , Stirrups Kathleen E. , Townsend Paul , Walker Neil , Webster Jennifer ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Butlertanaka Erika P. , Tanaka Yuri L. , Ito Jumpei , Uriu Keiya , Kosugi Yusuke , Suganami Mai , Oide Akiko , Yokoyama Miyabishara , Chiba Mika , Motozono Chihiro , Nasser Hesham , Shimizu Ryo , Kitazato Kazuko , Hasebe Haruyo , Irie Takashi , Nakagawa So , Wu Jiaqi , Takahashi Miyoko , Fukuhara Takasuke , Shimizu Kenta , Tsushima Kana , Kubo Haruko , Kazuma Yasuhiro , Nomura Ryosuke , Horisawa Yoshihito , Nagata Kayoko , Kawai Yugo , Yanagida Yohei , Tashiro Yusuke , Tokunaga Kenzo , Ozono Seiya , Kawabata Ryoko , Morizako Nanami , Sadamasu Kenji , Asakura Hiroyuki , Nagashima Mami , Yoshimura Kazuhisa ,   Ecuador-COVID19 Consortium, Cárdenas Paúl , Muñoz Erika , Barragan Veronica , Márquez Sully , Prado-Vivar Belén , Becerra-Wong Mónica , Caravajal Mateo , Trueba Gabriel , Rojas-Silva Patricio , Grunauer Michelle , Gutierrez Bernardo , Guadalupe Juan José , Fernández-Cadena Juan Carlos , Andrade-Molina Derly , Baldeon Manuel , Pinos Andrea , 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 , Goodfellow Ian G. , Matheson Nicholas J. , Sato Kei , Gupta Ravindra K. 
Published: February 2022

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.