Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity
Open accessPublished version of a preprint
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.
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- Authors
- Meng, B., Abdullahi, A., Ferreira, I. A. T. M., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P. P., Fatihi, S., Rathore, S., Zepeda, S. K., Papa, G., Kemp, S. A., Ikeda, T., Toyoda, M., Tan, T. S., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D. L., Charles, O. J., The CITIID-NIHR BioResource COVID-19 Collaboration, Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Ouwehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Maxwell, P., Shaw, A., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O’Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Gräf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O’Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Fawke, S., Gleadall, N., Grenfell, R., Hinch, A., Jackson, S., Jarvis, I., Krishna, B., Nice, F., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Stefanucci, L., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Butcher, H., Caputo, D., Chandler, M., Chinnery, P., Clapham-Riley, D., Dewhurst, E., Fernandez, C., Furlong, A., Graves, B., Gray, J., Hein, S., Ivers, T., Le Gresley, E., Linger, R., Kasanicki, M., King, R., Kingston, N., Meloy, S., Moulton, A., Muldoon, F., Ovington, N., Papadia, S., Penkett, C. J., Phelan, I., Ranganath, V., Paraschiv, R., Sage, A., Sambrook, J., Scholtes, I., Schon, K., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., The Genotype to Phenotype Japan (G2P-Japan) Consortium, Butlertanaka, E. P., Tanaka, Y. L., Ito, J., Uriu, K., Kosugi, Y., Suganami, M., Oide, A., Yokoyama, M., Chiba, M., Motozono, C., Nasser, H., Shimizu, R., Kitazato, K., Hasebe, H., Irie, T., Nakagawa, S., Wu, J., Takahashi, M., Fukuhara, T., Shimizu, K., Tsushima, K., Kubo, H., Kazuma, Y., Nomura, R., Horisawa, Y., Nagata, K., Kawai, Y., Yanagida, Y., Tashiro, Y., Tokunaga, K., Ozono, S., Kawabata, R., Morizako, N., Sadamasu, K., Asakura, H., Nagashima, M., Yoshimura, K., Ecuador-COVID19 Consortium, Cárdenas, P., Muñoz, E., Barragan, V., Márquez, S., Prado-Vivar, B., Becerra-Wong, M., Caravajal, M., Trueba, G., Rojas-Silva, P., Grunauer, M., Gutierrez, B., Guadalupe, J. J., Fernández-Cadena, J. C., Andrade-Molina, D., Baldeon, M., Pinos, A., Bowen, J. E., Joshi, A., Walls, A. C., Jackson, L., Martin, D., Smith, K. G. C., Bradley, J., Briggs, J. A. G., Choi, J., Madissoon, E., Meyer, K. B., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S. A., Fisher, A. J., Pizzuto, M. S., de Marco, A., Corti, D., Hosmillo, M., Lee, J. H., James, L. C., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I. G., Matheson, N. J., Sato, K., & Gupta, R. K.
- Affiliations
- University of Cambridge (GB)
- University of Miyazaki (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Institute of Genomics and Integrative Biology (IN)
- University of Washington (US)
- MRC Laboratory of Molecular Biology (GB)
- Joint Research Center for Human Retrovirus Infection, Kumamoto University (JP)
- National Institute of Genetics (JP)
- Kyoto University (JP)
- University College London (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Universidad San Francisco de Quito (EC)
- Hiroshima University (JP)
- Tokai University (JP)
- Hokkaido University (JP)
- National Institute of Infectious Diseases (JP)
- Tokyo Metropolitan Institute of Public Health (JP)
- Universidad Espíritu Santo (EC)
- Universidad Internacional del Ecuador (EC)
- Africa Health Research Institute (ZA)
- University of Cape Town (ZA)
- Max Planck Institute of Biochemistry (DE)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- European Bioinformatics Institute (GB)
- Wellcome Sanger Institute (GB)
- Newcastle University (GB)
- Vir Biotechnology (Switzerland) (CH)
- Howard Hughes Medical Institute (US)
- Max Planck Institute for Infection Biology (DE)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Sato, Kei
- Gupta, Ravindra K.
- ORCID
- Meng, Bo
- Abdullahi, Adam
- Ferreira, Isabella A. T. M.
- Goonawardane, Niluka
- Saito, Akatsuki
- Gerber, Pehuén Pereyra
- Fatihi, Saman
- Rathore, Surabhi
- Zepeda, Samantha K.
- Papa, Guido
- Kemp, Steven A.
- Ikeda, Terumasa
- Tan, Toong Seng
- Kuramochi, Jin
- Ueno, Takamasa
- Shirakawa, Kotaro
- Brevini, Teresa
- Mallery, Donna L.
- Charles, Oscar J.
- Baker, Stephen
- Hess, Christoph
- Lehner, Paul J.
- Lyons, Paul A.
- Ouwehand, Willem H.
- Summers, Charlotte
- Thaventhiran, James E. D.
- Toshner, Mark
- Weekes, Michael P.
- Maxwell, Patrick
- Shaw, Ashley
- Domingo, Jason
- Kennet, Jane
- Price, Jane
- Rowlands, Jane
- Dunmore, Benjamin J.
- Gräf, Stefan
- Legchenko, Ekaterina
- Martin, Jennifer
- Mescia, Federica
- Pointon, Linda
- Tilly, Tobias
- Cossetti, Chiara
- Epping, Madeline
- Fawke, Stuart
- Grenfell, Richard
- Jackson, Sarah
- Nice, Francesca
- Omarjee, Ommar
- Perera, Marianne
- Potts, Martin
- Richoz, Nathan
- Stefanucci, Luca
- Bunclark, Katherine
- Chinnery, Patrick
- Papadia, Sofia
- Penkett, Christopher J.
- Schon, Katherine
- Stark, Hannah
- Stirrups, Kathleen E.
- Walker, Neil
- Webster, Jennifer
- Butlertanaka, Erika P.
- Tanaka, Yuri L.
- Ito, Jumpei
- Motozono, Chihiro
- Nasser, Hesham
- Irie, Takashi
- Nakagawa, So
- Wu, Jiaqi
- Fukuhara, Takasuke
- Shimizu, Kenta
- Kazuma, Yasuhiro
- Nomura, Ryosuke
- Tashiro, Yusuke
- Tokunaga, Kenzo
- Ozono, Seiya
- Sadamasu, Kenji
- Asakura, Hiroyuki
- Nagashima, Mami
- Yoshimura, Kazuhisa
- Cárdenas, Paúl
- Muñoz, Erika
- Márquez, Sully
- Becerra-Wong, Mónica
- Trueba, Gabriel
- Grunauer, Michelle
- Guadalupe, Juan José
- Andrade-Molina, Derly
- Baldeon, Manuel
- Bowen, John E.
- Walls, Alexandra C.
- Jackson, Laurelle
- Martin, Darren
- Smith, Kenneth G. C.
- Bradley, John
- Briggs, John A. G.
- Choi, Jinwook
- Madissoon, Elo
- Meyer, Kerstin B.
- Teichmann, Sarah A.
- Fisher, Andrew J.
- Pizzuto, Matteo S.
- Corti, Davide
- Hosmillo, Myra
- James, Leo C.
- Thukral, Lipi
- Veesler, David
- Sigal, Alex
- Sampaziotis, Fotios
- Goodfellow, Ian G.
- Sato, Kei
- Gupta, Ravindra K.
- Venue
- Nature
- Published
- 2022-02-01
- Volume
- 603
- Issue
- 7902
- Pages
- 706-714
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8942856
- OpenAlex
- W4210665241
- Cited by
- 1,146
- References
- 12
- Citations by year
- 2026: 69 · 2025: 122 · 2024: 215 · 2023: 357 · 2022: 380 · 2021: 2 · 2020: 1
- FWCI
- 131.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, other-oa)
- Griffith Research Online (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- Bill and Melinda Gates Foundation (OPP1156262, INV-018944)
- Takeda Science Foundation
- NHS Blood and Transplant (207498/Z/17/Z, WPA15‐02)
- Japan Agency for Medical Research and Development (20fk0108163, 20fk0108451h0001, JPJSCCA20190008, CREST, 21fk0410033, 20fk0108413h0001, 20fk0108146, 21fk0410039, 20fk0108270h0001, 20wm0325009, 21wm0325009)
- Wellcome Trust (223054/Z/21/Z, 108082/A/15/Z, Z/17/Z, HHSN272201700059C, 107633/Z/15/Z, WT108082AIA, MR/W005611/1, DEL-15-006, 200594/Z/16/Z, 207498, DP1AI158186, 207498/Z/17/Z)
- Tokyo Biochemical Research Foundation
- UK Research and Innovation (MR/W005611/1/)
- Fast Grants
- National Institute for Health and Care Research (RG94028, NF-SI-0514-10109, 207498, RG85445, CL-2017-14-001)
- Department of Health and Social Care (HHSN272201700059C)
- Academy of Medical Sciences (SGL019\1071)
- University of Cambridge
- Newcastle University
- Rosetrees Trust
- South African Medical Research Council (6084-CO-AP-2020, DEL-15-006)
- Mitsubishi Foundation
- European Association for the Study of the Liver
- National Institutes of Health (COVID-19, OPP1156262, HHSN272201700059C)
- NIHR BioResource
- Medical Research Council (MR/T032413/1, MR/P008801/1, MR/W005611/1, MC_PC_17230, COVID-19, 207498/Z/17/Z)
- Engineering and Physical Sciences Research Council (EP/V002910/1, MR/W005611/1)
- Japan Society for the Promotion of Science (18H02662, 23K24378, 18KK0447, 21K07060, JPJSCCA20190008, CREST, 21H02737, DC1 19J20488, 19J20488, 19K06382)
- Research Institute for Microbial Diseases, Osaka University
- National Institute of General Medical Sciences (T32GM008268)
- National Institute of Allergy and Infectious Diseases (HHSN272201700059C, COVID-19, DP1AI158186, OPP1156262, R01AI138546)
- Institute of Genetics
- Core Research for Evolutional Science and Technology (JPMJCR20H4)
- Strategic International Collaborative Research Program
- Health Data Research UK
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Keywords
- SARS-CoV-2 Omicron BA.1, TMPRSS2, spike protein cleavage, viral entry, syncytium formation, ACE2 binding affinity, neutralizing antibodies, vaccine escape, remdesivir, molnupiravir, cell tropism, nasal epithelial cells, spike protein mutations
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