Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.
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Authors
Meng, Bo
Abdullahi, Adam
Ferreira, Isabella ATM
Goonawardane, Niluka
Saito, Akatsuki
Kimura, Izumi
Yamasoba, Daichi
Gerber, Pehuén Pereyra
Fatihi, Saman
Rathore, Surabhi
Zepeda, Samantha K
Papa, Guido
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
CITIID-NIHR BioResource COVID-19 Collaboration
Genotype to Phenotype Japan (G2P-Japan) Consortium
Ecuador-COVID19 Consortium
Bowen, John E
Joshi, Anshu
Walls, Alexandra C
Jackson, Laurelle
Martin, Darren
Bradley, John
Briggs, John AG
Choi, Jinwook
Madissoon, Elo
Meyer, Kerstin B
Mlcochova, Petra
Ceron-Gutierrez, Lourdes
Doffinger, Rainer
Fisher, Andrew J
Pizzuto, Matteo S
de Marco, Anna
Corti, Davide
James, Leo C
Thukral, Lipi
Veesler, David
Sigal, Alex
Goodfellow, Ian G
Matheson, Nicholas J
Sato, Kei
Publication Date
2022-03Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Type
Article
This Version
AM
Later Version(s)
Metadata
Show full item recordCitation
Meng, B., Abdullahi, A., Ferreira, I. A., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., et al. (2022). Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.. Nature https://doi.org/10.1038/s41586-022-04474-x
Abstract
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.
Sponsorship
Wellcome Trust (108082/A/15/Z)
Wellcome Trust (207498/Z/17/Z)
Medical Research Council (MC_PC_17230)
MRC (via Imperial College London) (MR/W005611/1)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41586-022-04474-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333671
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