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dc.contributor.authorMeng, Bo
dc.contributor.authorAbdullahi, Adam
dc.contributor.authorFerreira, Isabella ATM
dc.contributor.authorGoonawardane, Niluka
dc.contributor.authorSaito, Akatsuki
dc.contributor.authorKimura, Izumi
dc.contributor.authorYamasoba, Daichi
dc.contributor.authorGerber, Pehuén Pereyra
dc.contributor.authorFatihi, Saman
dc.contributor.authorRathore, Surabhi
dc.contributor.authorZepeda, Samantha K
dc.contributor.authorPapa, Guido
dc.contributor.authorKemp, Steven
dc.contributor.authorIkeda, Terumasa
dc.contributor.authorToyoda, Mako
dc.contributor.authorTan, Toong Seng
dc.contributor.authorKuramochi, Jin
dc.contributor.authorMitsunaga, Shigeki
dc.contributor.authorUeno, Takamasa
dc.contributor.authorShirakawa, Kotaro
dc.contributor.authorTakaori-Kondo, Akifumi
dc.contributor.authorBrevini, Teresa
dc.contributor.authorMallery, Donna L
dc.contributor.authorCharles, Oscar J
dc.contributor.authorCITIID-NIHR BioResource COVID-19 Collaboration
dc.contributor.authorGenotype to Phenotype Japan (G2P-Japan) Consortium
dc.contributor.authorEcuador-COVID19 Consortium
dc.contributor.authorBowen, John E
dc.contributor.authorJoshi, Anshu
dc.contributor.authorWalls, Alexandra C
dc.contributor.authorJackson, Laurelle
dc.contributor.authorMartin, Darren
dc.contributor.authorSmith, Kenneth
dc.contributor.authorBradley, John
dc.contributor.authorBriggs, John AG
dc.contributor.authorChoi, Jinwook
dc.contributor.authorMadissoon, Elo
dc.contributor.authorMeyer, Kerstin B
dc.contributor.authorMlcochova, Petra
dc.contributor.authorCeron-Gutierrez, Lourdes
dc.contributor.authorDoffinger, Rainer
dc.contributor.authorTeichmann, Sarah
dc.contributor.authorFisher, Andrew J
dc.contributor.authorPizzuto, Matteo S
dc.contributor.authorde Marco, Anna
dc.contributor.authorCorti, Davide
dc.contributor.authorHosmillo, Myra
dc.contributor.authorLee, Joo
dc.contributor.authorJames, Leo C
dc.contributor.authorThukral, Lipi
dc.contributor.authorVeesler, David
dc.contributor.authorSigal, Alex
dc.contributor.authorSampaziotis, Fotios
dc.contributor.authorGoodfellow, Ian G
dc.contributor.authorMatheson, Nicholas J
dc.contributor.authorSato, Kei
dc.contributor.authorGupta, Ravindra
dc.date.accessioned2022-03-31T16:29:16Z
dc.date.available2022-03-31T16:29:16Z
dc.date.issued2022-03
dc.date.submitted2021-12-21
dc.identifier.issn0028-0836
dc.identifier.others41586-022-04474-x
dc.identifier.other4474
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335575
dc.description.abstractThe 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.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectArticle
dc.subject/631/326/596/4130
dc.subject/631/250/2161
dc.subject/13
dc.subject/13/1
dc.subject/14/10
dc.subject/82/1
dc.subject/82/83
dc.subject/82/80
dc.subject/14/35
dc.subject/14/19
dc.subject/13/106
dc.subject/13/100
dc.subjectarticle
dc.titleAltered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.
dc.typeArticle
dc.date.updated2022-03-31T16:29:15Z
prism.endingPage714
prism.issueIdentifier7902
prism.publicationNameNature
prism.startingPage706
prism.volume603
dc.identifier.doi10.17863/CAM.83006
dcterms.dateAccepted2022-01-26
rioxxterms.versionofrecord10.1038/s41586-022-04474-x
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidKemp, Steven [0000-0001-7077-6793]
dc.contributor.orcidSmith, Kenneth [0000-0003-3829-4326]
dc.contributor.orcidBradley, John [0000-0002-7774-8805]
dc.contributor.orcidTeichmann, Sarah [0000-0002-6294-6366]
dc.contributor.orcidHosmillo, Myra [0000-0002-3514-7681]
dc.contributor.orcidLee, Joo [0000-0002-7364-6422]
dc.contributor.orcidSampaziotis, Fotios [0000-0003-0812-7586]
dc.contributor.orcidGupta, Ravindra [0000-0001-9751-1808]
dc.identifier.eissn1476-4687
pubs.funder-project-idWellcome Trust (108082/A/15/Z)
pubs.funder-project-idWellcome Trust (207498/Z/17/Z)
pubs.funder-project-idMedical Research Council (MC_PC_17230)
pubs.funder-project-idMRC (via Imperial College London) (MR/W005611/1)
pubs.funder-project-idMedical Research Council (MR/P008801/1)
cam.issuedOnline2022-02-01


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