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The S protein expresses an RGD motif, suggesting that integrins may be co-receptors. Here, we UV-inactivated SARS-CoV-2 and fluorescently labeled the envelope membrane with octadecyl rhodamine B (R18) to explore the role of integrin activation in mediating cell entry and productive infection. We used flow cytometry and confocal microscopy to show that SARS-CoV-2\n                    <jats:sup>R18<\/jats:sup>\n                    particles engage basal-state integrins. Furthermore, we demonstrate that Mn\n                    <jats:sup>2+<\/jats:sup>\n                    , which induces integrin extension, enhances cell entry of SARS-CoV-2\n                    <jats:sup>R18<\/jats:sup>\n                    . We also show that one class of integrin antagonist, which binds to the \u03b1I MIDAS site and stabilizes the inactive, closed conformation, selectively inhibits the engagement of SARS-CoV-2\n                    <jats:sup>R18<\/jats:sup>\n                    with basal state integrins, but is ineffective against Mn\n                    <jats:sup>2+<\/jats:sup>\n                    -activated integrins. RGD-integrin antagonists inhibited SARS-CoV-2\n                    <jats:sup>R18<\/jats:sup>\n                    binding regardless of integrin activation status. Integrins transmit signals bidirectionally: 'inside-out' signaling primes the ligand-binding function of integrins via a talin-dependent mechanism, and 'outside-in' signaling occurs downstream of integrin binding to macromolecular ligands. Outside-in signaling is mediated by G\u03b1\n                    <jats:sub>13<\/jats:sub>\n                    . Using cell-permeable peptide inhibitors of talin and G\u03b1\n                    <jats:sub>13<\/jats:sub>\n                    binding to the cytoplasmic tail of an integrin's \u03b2 subunit, we demonstrate that talin-mediated signaling is essential for productive infection.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-99893-7","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T06:09:16Z","timestamp":1634191756000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Integrin activation is an essential component of SARS-CoV-2 infection"],"prefix":"10.1038","volume":"11","author":[{"given":"Peter","family":"Simons","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek A.","family":"Rinaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Bondu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M.","family":"Kell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Bradfute","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane S.","family":"Lidke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tione","family":"Buranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"99893_CR1","unstructured":"WHO https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it (2020)."},{"key":"99893_CR2","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","volume":"395","author":"F Zhou","year":"2020","unstructured":"Zhou, F. et al. 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