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During periodontitis pathobionts such as\n                    <jats:italic>Pg<\/jats:italic>\n                    can enter the bloodstream and growing evidence correlates periodontitis with increased risk of cardiovascular and neurodegenerative diseases. However, the mechanism by which immune cells respond to\n                    <jats:italic>Pg<\/jats:italic>\n                    challenge\n                    <jats:italic>in vivo<\/jats:italic>\n                    remains elusive.\n                    <jats:italic>Pg<\/jats:italic>\n                    produce aggressive proteolytic virulence factors termed gingipains which not only provide nutrients necessary for bacterial growth, but also subvert the host immune response, facilitating bacterial survival. Using transgenic zebrafish with fluorescently labelled macrophages and neutrophils, the role of gingipains in bacterial survival and interaction with phagocytes during systemic and local infection was examined. In contrast to the wild-type (W83)\n                    <jats:italic>Pg<\/jats:italic>\n                    , isogenic gingipain-null (\n                    <jats:italic>\u0394K\/R-ab)<\/jats:italic>\n                    or wild-type\n                    <jats:italic>Pg<\/jats:italic>\n                    treated with gingipain inhibitors caused less zebrafish mortality, bacteria were rapidly phagocytosed, acidified in phagosomes and eradicated when systemically injected, showing that gingipains are instrumental in preventing phagocytosis and intracellular killing of\n                    <jats:italic>Pg<\/jats:italic>\n                    by innate immune cells. Moreover,\n                    <jats:italic>Pg<\/jats:italic>\n                    were predominantly phagocytosed by macrophages, and gingipain depletion\/inactivation increased bacterial phagocytosis when bacteria were injected either systemically or locally in the otic vesicle, with less bacteria internalised by neutrophils. This phenomenon was\n                    <jats:italic>Pg<\/jats:italic>\n                    -specific as\n                    <jats:italic>Fusobacterium nucleatum<\/jats:italic>\n                    caused neutrophil recruitment that then effectively phagocytosed these bacteria. These data demonstrate the important role of phagocytes, especially macrophages, in combating\n                    <jats:italic>Pg<\/jats:italic>\n                    infection and highlight the crucial protective role of gingipains in subverting the innate immune response. This study also emphasizes the advantages of using zebrafish to study interactions of\n                    <jats:italic>Pg<\/jats:italic>\n                    with phagocytes\n                    <jats:italic>in vivo<\/jats:italic>\n                    in real-time, providing a valuable experimental system for testing new therapeutic strategies aimed at reducing periodontal-associated systemic or neurodegenerative disease.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012821","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T13:30:41Z","timestamp":1737466241000},"page":"e1012821","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":26,"title":["Gingipains protect Porphyromonas gingivalis from macrophage-mediated phagocytic clearance"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3979-949X","authenticated-orcid":true,"given":"Magdalena","family":"Widziolek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mieszkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Marcinkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartlomiej","family":"Salamaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Folkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Rakus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Chadzinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Potempa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham P.","family":"Stafford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz K.","family":"Prajsnar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Murdoch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,21]]},"reference":[{"issue":"1","key":"ppat.1012821.ref001","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/prd.12362","article-title":"Microbial signatures of health, gingivitis, and periodontitis","volume":"86","author":"L Abusleme","year":"2021","journal-title":"Periodontol 2000"},{"issue":"1","key":"ppat.1012821.ref002","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/prd.12371","article-title":"Polymicrobial communities in periodontal disease: Their quasi-organismal nature and dialogue with the host","volume":"86","author":"G Hajishengallis","year":"2021","journal-title":"Periodontol 2000"},{"issue":"10","key":"ppat.1012821.ref003","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nrmicro2873","article-title":"The keystone-pathogen hypothesis","volume":"10","author":"G Hajishengallis","year":"2012","journal-title":"Nat Rev Microbiol"},{"issue":"6","key":"ppat.1012821.ref004","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1902\/jop.1987.58.6.417","article-title":"The presence of bacteria in the oral epithelium in periodontal disease. 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