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

Lookup NU author(s): Teresa Brevini, Professor Andrew FisherORCiD, Dr Fotis Sampaziotis

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2022. The Author(s). 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.


Publication metadata

Author(s): Meng B, Abdullahi A, Ferreira IATM, Goonawardane N, Saito A, Kimura I, Yamasoba D, Gerber PP, Fatihi S, Rathore S, Zepeda SK, Papa G, Kemp SA, Ikeda T, Toyoda M, Tan TS, Kuramochi J, Mitsunaga S, Ueno T, Shirakawa K, Takaori-Kondo A, Brevini T, Mallery DL, Charles OJ, Bowen JE, Joshi A, Walls AC, Jackson L, Martin D, Smith KGC, Bradley J, Briggs JAG, Choi J, Madissoon E, Meyer KB, Mlcochova P, Ceron-Gutierrez L, Doffinger R, Teichmann SA, Fisher AJ, Pizzuto MS, de Marco A, Corti D, Hosmillo M, Lee JH, James LC, Thukral L, Veesler D, Sigal A, Sampaziotis F, Goodfellow IG, Matheson NJ, Sato K, Gupta RK

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2022

Volume: 603

Issue: 7902

Pages: 706-714

Print publication date: 24/03/2022

Online publication date: 01/02/2022

Acceptance date: 26/01/2022

Date deposited: 26/04/2022

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41586-022-04474-x

DOI: 10.1038/s41586-022-04474-x

PubMed id: 35104837


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Funding

Funder referenceFunder name
5T32GM008268-32
6084-CO-AP-2020
DP1AI158186
HHSN272201700059C
INV-018944
OPP1156262
R01 AI138546
RG94028
RG85445

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