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How infection is recognized during Thoeris immunity is not known. Here we investigate the staphylococcal Thoeris defense system, ThsA\u2013B1\u2013B2, and found that, upon infection, the major capsid proteins of\n                    <jats:italic>Siphoviridae<\/jats:italic>\n                    phages from serogroup B, but not A, form a complex with ThsB1 and ThsB2 to activate Thoeris defense. Thoeris cyclases from\n                    <jats:italic>Streptococcus<\/jats:italic>\n                    also recognize major capsid proteins. Our results suggest that the accumulation of capsid mutations that enable avoidance of Thoeris recognition may be an important evolutionary force behind the structural diversity of prokaryotic viruses. More broadly, given that some mammalian immune pathways contain Toll\/interleukin-1 receptor domains that recognize viral structures, our findings highlight a conserved mechanism of innate antiviral immunity.\n                  <\/jats:p>","DOI":"10.1038\/s41564-025-02150-0","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T09:03:48Z","timestamp":1761296628000},"page":"2892-2902","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Bacterial TIR-based immune systems sense phage capsids to initiate defense"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0115-7013","authenticated-orcid":false,"given":"Cameron G.","family":"Roberts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe B.","family":"Fishman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8167-9358","authenticated-orcid":false,"given":"Dalton V.","family":"Banh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9779-7778","authenticated-orcid":false,"given":"Dinshaw J.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9163-0969","authenticated-orcid":false,"given":"Luciano A.","family":"Marraffini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"2150_CR1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/s41577-022-00705-4","volume":"22","author":"T Wein","year":"2022","unstructured":"Wein, T. & Sorek, R. Bacterial origins of human cell-autonomous innate immune mechanisms. Nat. Rev. Immunol. 22, 629\u2013638 (2022).","journal-title":"Nat. Rev. Immunol."},{"key":"2150_CR2","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.cell.2020.02.041","volume":"180","author":"KA Fitzgerald","year":"2020","unstructured":"Fitzgerald, K. A. & Kagan, J. C. Toll-like receptors and the control of immunity. Cell 180, 1044\u20131066 (2020).","journal-title":"Cell"},{"key":"2150_CR3","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1126\/science.aax1911","volume":"365","author":"S Horsefield","year":"2019","unstructured":"Horsefield, S. et al. NAD(+) cleavage activity by animal and plant TIR domains in cell death pathways. Science 365, 793\u2013799 (2019).","journal-title":"Science"},{"key":"2150_CR4","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1126\/science.aax1771","volume":"365","author":"L Wan","year":"2019","unstructured":"Wan, L. et al. 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The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}