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

Meng, B., Abdullahi, A., Ferreira, I. A. T. M., Goonawardane, N., Saito, A., Kimura, I., et al. (2022). Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature, 603, 706-714. doi:10.1038/s41586-022-04474-x.

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 Creators:
Meng, Bo1, Author
Abdullahi, Adam1, Author
Ferreira, Isabella A. T. M.1, Author
Goonawardane, Niluka1, Author
Saito, Akatsuki1, Author
Kimura, Izumi1, Author
Yamasoba, Daichi1, Author
Gerber, Pehuen Pereyra1, Author
Fatihi, Saman1, Author
Rathore, Surabhi1, Author
Zepeda, Samantha K.1, Author
Papa, Guido1, Author
Kemp, Steven A.1, Author
Ikeda, Terumasa1, Author
Toyoda, Mako1, Author
Tan, Toong Seng1, Author
Kuramochi, Jin1, Author
Mitsunaga, Shigeki1, Author
Ueno, Takamasa1, Author
Shirakawa, Kotaro1, Author
Takaori-Kondo, Akifumi1, AuthorBrevini, Teresa1, AuthorMallery, Donna L.1, AuthorCharles, Oscar J.1, AuthorBowen, John E.1, AuthorJoshi, Anshu1, AuthorWalls, Alexandra C.1, AuthorJackson, Laurelle1, AuthorMartin, Darren1, AuthorSmith, Kenneth G. C.1, AuthorBradley, John1, AuthorBriggs, John A. G.2, Author           Choi, Jinwook1, AuthorMadissoon, Elo1, AuthorMeyer, Kerstin B.1, AuthorMlcochova, Petra1, AuthorCeron-Gutierrez, Lourdes1, AuthorDoffinger, Rainer1, AuthorTeichmann, Sarah A.1, AuthorFisher, Andrew J.1, AuthorPizzuto, Matteo S.1, Authorde Marco, Anna1, AuthorCorti, Davide1, AuthorHosmillo, Myra1, AuthorLee, Joo Hyeon1, AuthorJames, Leo C.1, AuthorThukral, Lipi1, AuthorVeesler, David1, AuthorSigal, Alex1, AuthorSampaziotis, Fotios1, AuthorGoodfellow, Ian G.1, AuthorMatheson, Nicholas J.1, AuthorSato, Kei1, AuthorGupta, Ravindra K.1, Author more..
Affiliations:
1external, ou_persistent22              
2Briggs, John / Cell and Virus Structure, Max Planck Institute of Biochemistry, Max Planck Society, ou_3344661              

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Free keywords: ACE2; VISUALIZATION; PERFORMANCE; ALIGNMENT; RECEPTOR; L452RScience & Technology - Other Topics;
 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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Language(s): eng - English
 Dates: 2022-03
 Publication Status: Published in print
 Pages: 30
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 603 Sequence Number: - Start / End Page: 706 - 714 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238