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タイトル: | Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity |
著者: | Meng, Bo Abdullahi, Adam Ferreira, Isabella A. T. M. Goonawardane, Niluka Saito, Akatsuki Kimura, Izumi Yamasoba, Daichi Gerber, Pehuén Pereyra Fatihi, Saman Rathore, Surabhi Zepeda, Samantha K. Papa, Guido Kemp, Steven A. Ikeda, Terumasa Toyoda, Mako Tan, Toong Seng Kuramochi, Jin Mitsunaga, Shigeki Ueno, Takamasa Shirakawa, Kotaro https://orcid.org/0000-0002-7469-1276 (unconfirmed) Takaori-Kondo, Akifumi Brevini, Teresa Mallery, Donna L. Charles, Oscar J. The CITIID-NIHR BioResource COVID-19 Collaboration The Genotype to Phenotype Japan (G2P-Japan) Consortium Ecuador-COVID19 Consortium Bowen, John E. Joshi, Anshu Walls, Alexandra C. Jackson, Laurelle Martin, Darren Smith, Kenneth G. C. Bradley, John Briggs, John A. G. Choi, Jinwook Madissoon, Elo Meyer, Kerstin Mlcochova, Petra Ceron-Gutierrez, Lourdes Doffinger, Rainer Teichmann, Sarah A. Fisher, Andrew J. Pizzuto, Matteo S. de Marco, Anna Corti, Davide Hosmillo, Myra Lee, Joo Hyeon James, Leo C. Thukral, Lipi Veesler, David Sigal, Alex Sampaziotis, Fotios Goodfellow, Ian G. Matheson, Nicholas J. Sato, Kei Gupta, Ravindra K. |
著者名の別形: | 齊藤, 暁 木村, 出海 山岨, 大智 池田, 輝政 豊田, 真子 倉持, 仁 光永, 滋樹 上野, 貴将 白川, 康太郎 髙折, 晃史 佐藤, 佳 |
キーワード: | Immune evasion SARS-CoV-2 |
発行日: | 24-Mar-2022 |
出版者: | Springer Nature |
誌名: | Nature |
巻: | 603 |
号: | 7902 |
開始ページ: | 706 |
終了ページ: | 714 |
抄録: | The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and bears multiple spike mutations2. Here we show that Omicron spike has higher affinity for ACE2 compared to Delta as well as a marked change of antigenicity conferring 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 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 lower airway organoids, lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared to Delta. Replication differences mapped to entry efficiency using spike pseudotyped virus (PV) assays. The defect for Omicron PV to enter specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and knock down of TMPRSS2 impacted Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that promotes cell entry via plasma membrane fusion, with greater dependency on cell entry via the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was markedly impaired compared to the Delta spike. Omicron’s less efficient spike cleavage at S1/S2 is associated with shift in cellular tropism away from TMPRSS2 expressing cells, with implications for altered pathogenesis. |
記述: | SARS-CoV-2オミクロン株による中和抗体回避と感染指向性の変化. 京都大学プレスリリース. 2022-02-03. |
著作権等: | © The Author(s) 2022 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. |
URI: | http://hdl.handle.net/2433/275415 |
DOI(出版社版): | 10.1038/s41586-022-04474-x |
PubMed ID: | 35104837 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2022-02-03-0 |
出現コレクション: | 学術雑誌掲載論文等 |
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