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Here, we demonstrate that miropin directly inhibits the lysine-specific gingipain Kgp and the calpain-like protease Tpr produced by\n                    <jats:italic>Pg<\/jats:italic>\n                    , forming irreversible covalent inhibitory complexes. While recombinant native miropin impairs\n                    <jats:italic>Pg<\/jats:italic>\n                    growth, an engineered variant targeting both lysine- and arginine-specific gingipains entirely abolishes bacterial growth in a defined medium. In vivo, recombinant miropin reduces\n                    <jats:italic>Pg<\/jats:italic>\n                    virulence and, when co-infected with wild-type\n                    <jats:italic>Tf<\/jats:italic>\n                    , prevents lethal infection and significantly reduces alveolar bone loss, but not when co-infected with a miropin-deficient mutant. Protection is associated with inhibition of gingipain activity and normalization of the RANKL\/OPG ratio in periodontal tissues. These findings identify miropin as a potent interspecies virulence modulator and challenge the prevailing view of\n                    <jats:italic>Tf<\/jats:italic>\n                    as an exclusively pathogenic member of the oral microbiome.\n                  <\/jats:p>","DOI":"10.1038\/s44319-026-00958-3","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:05:14Z","timestamp":1791903914000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interspecies regulation of virulence through gingipain inhibition by a Tannerella forsythia serpin"],"prefix":"10.1038","author":[{"given":"Miros\u0142aw","family":"Ksi\u0105\u017cek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5432-8739","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Benedyk-Machaczka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danuta","family":"Mizgalska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicja","family":"Sochaj-Gregorczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Walig\u00f3rska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9281-1827","authenticated-orcid":false,"given":"Kamila","family":"Drzazga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Nowak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kaczor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Potempa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida B","family":"Th\u00f8gersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9292-9172","authenticated-orcid":false,"given":"Jan J","family":"Enghild","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Scavenius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Mydel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7031-4249","authenticated-orcid":false,"given":"Savannah C","family":"Moris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6185-1915","authenticated-orcid":false,"given":"Juhi","family":"Bagaitkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3600-7461","authenticated-orcid":false,"given":"Jan","family":"Potempa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"958_CR1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jim.2013.05.002","volume":"394","author":"T Abe","year":"2013","unstructured":"Abe T, Hajishengallis G (2013) Optimization of the ligature-induced periodontitis model in mice. 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Dr. Potempa, Dr. Ksiazek, Dr. Mizgalska and Dr. Benedyk-Machaczka has a patent application on miropins.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}