{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360021393313584640.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1101/2021.12.17.473248"}},{"identifier":{"@type":"URI","@value":"https://syndication.highwire.org/content/doi/10.1101/2021.12.17.473248"}},{"identifier":{"@type":"DOI","@value":"10.60692/kqex3-tcg35"}},{"identifier":{"@type":"DOI","@value":"10.60692/f58yy-8g916"}}],"resourceType":"preprint","dc:title":[{"@value":"SARS-CoV-2 Omicron spike mediated immune escape and tropism shift"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title>\n                <jats:p>The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380021393313584664","@type":"Researcher","foaf:name":[{"@value":"Bo Meng"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584671","@type":"Researcher","foaf:name":[{"@value":"Isabella A.T.M Ferreira"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584659","@type":"Researcher","foaf:name":[{"@value":"Adam Abdullahi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584691","@type":"Researcher","foaf:name":[{"@value":"Niluka Goonawardane"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584687","@type":"Researcher","foaf:name":[{"@value":"Akatsuki Saito"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584684","@type":"Researcher","foaf:name":[{"@value":"Izumi Kimura"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584675","@type":"Researcher","foaf:name":[{"@value":"Daichi Yamasoba"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584652","@type":"Researcher","foaf:name":[{"@value":"Pehuén Perera Gerba"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584655","@type":"Researcher","foaf:name":[{"@value":"Saman Fatihi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584642","@type":"Researcher","foaf:name":[{"@value":"Surabhi Rathore"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584692","@type":"Researcher","foaf:name":[{"@value":"Samantha K Zepeda"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584680","@type":"Researcher","foaf:name":[{"@value":"Guido Papa"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584679","@type":"Researcher","foaf:name":[{"@value":"Steven A. Kemp"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584690","@type":"Researcher","foaf:name":[{"@value":"Terumasa Ikeda"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584647","@type":"Researcher","foaf:name":[{"@value":"Mako Toyoda"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584651","@type":"Researcher","foaf:name":[{"@value":"Toong Seng Tan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584678","@type":"Researcher","foaf:name":[{"@value":"Jin Kuramochi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584660","@type":"Researcher","foaf:name":[{"@value":"Shigeki Mitsunaga"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584653","@type":"Researcher","foaf:name":[{"@value":"Takamasa Ueno"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584681","@type":"Researcher","foaf:name":[{"@value":"Kotaro Shirakawa"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584657","@type":"Researcher","foaf:name":[{"@value":"Akifumi Takaori-Kondo"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584682","@type":"Researcher","foaf:name":[{"@value":"Teresa Brevini"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584685","@type":"Researcher","foaf:name":[{"@value":"Donna L. Mallery"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584673","@type":"Researcher","foaf:name":[{"@value":"Oscar J. Charles"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584646","@type":"Researcher","foaf:name":[{"@value":"John E Bowen"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584645","@type":"Researcher","foaf:name":[{"@value":"Anshu Joshi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584672","@type":"Researcher","foaf:name":[{"@value":"Alexandra C. Walls"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584693","@type":"Researcher","foaf:name":[{"@value":"Laurelle Jackson"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584665","@type":"Researcher","foaf:name":[{"@value":"Sandile Cele"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584686","@type":"Researcher","foaf:name":[{"@value":"Darren Martin"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584658","@type":"Researcher","foaf:name":[{"@value":"Kenneth G.C. Smith"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584640","@type":"Researcher","foaf:name":[{"@value":"John Bradley"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584641","@type":"Researcher","foaf:name":[{"@value":"John A. G. Briggs"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584662","@type":"Researcher","foaf:name":[{"@value":"Jinwook Choi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584668","@type":"Researcher","foaf:name":[{"@value":"Elo Madissoon"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584670","@type":"Researcher","foaf:name":[{"@value":"Kerstin Meyer"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584669","@type":"Researcher","foaf:name":[{"@value":"Petra Mlcochova"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584643","@type":"Researcher","foaf:name":[{"@value":"Lourdes Ceron-Gutierrez"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584648","@type":"Researcher","foaf:name":[{"@value":"Rainer Doffinger"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584644","@type":"Researcher","foaf:name":[{"@value":"Sarah Teichmann"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584649","@type":"Researcher","foaf:name":[{"@value":"Matteo Pizzuto"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584667","@type":"Researcher","foaf:name":[{"@value":"Anna de Marco"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584666","@type":"Researcher","foaf:name":[{"@value":"Davide Corti"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584663","@type":"Researcher","foaf:name":[{"@value":"Alex Sigal"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584674","@type":"Researcher","foaf:name":[{"@value":"Leo James"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584661","@type":"Researcher","foaf:name":[{"@value":"David Veesler"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584677","@type":"Researcher","foaf:name":[{"@value":"Myra Hosmillo"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584676","@type":"Researcher","foaf:name":[{"@value":"Joo Hyeon Lee"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584650","@type":"Researcher","foaf:name":[{"@value":"Fotios Sampaziotis"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584656","@type":"Researcher","foaf:name":[{"@value":"Ian G Goodfellow"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584683","@type":"Researcher","foaf:name":[{"@value":"Nicholas J. Matheson"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584688","@type":"Researcher","foaf:name":[{"@value":"Lipi Thukral"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584689","@type":"Researcher","foaf:name":[{"@value":"Kei Sato"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021393313584654","@type":"Researcher","foaf:name":[{"@value":"Ravindra K. 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