{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:46:32Z","timestamp":1791243992691,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013315","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000}}],"reference-count":73,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1583; A05"],"award-info":[{"award-number":["SFB1583; A05"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1583; B01"],"award-info":[{"award-number":["SFB1583; B01"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["ERC-2018-ADG\/NCI-CAD"],"award-info":[{"award-number":["ERC-2018-ADG\/NCI-CAD"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Interferon-\u03b3 (IFN-\u03b3) is an immunoregulatory cytokine essential for cellular immunity against intracellular pathogens, including <jats:italic>Chlamydia<\/jats:italic>. Interferon-stimulated gene (ISG) 15, a member of the ubiquitin family, contributes to host resistance to viral and bacterial infections. ISG15 can exist either in an unconjugated form or covalently attached to host proteins through a process known as ISGylation. Here, we show that infection with <jats:italic>Chlamydia trachomatis<\/jats:italic> (Ct) induces the expression and secretion of ISG15 in human primary cells and mouse female genital tract (FGT) organoids. ISG15 secretion by genital tract epithelial cells resulted in increased IFN-\u03b3 release from natural killer (NK) cells. The production of IFN-\u03b3 by NK cells in response to ISG15 was completely abolished in NK cells lacking the interleukin-18 receptor alpha (IL-18Ra), demonstrating a co-stimulatory effect of ISG15 with IL-18 in enhancing IFN-\u03b3 release. ISG15 was secreted into the FGT and was involved in controlling bacterial load in a murine infection model. Furthermore, ISG15 reduced macrophage responsiveness to IFN-\u03b3 as an M1-polarizing signal for pro-inflammatory responses, potentially \u201cshielding\u201d macrophages from excessive IFN-\u03b3. Evidence of uterine horn pathology and reduced IL-10 levels in the FGT of infected ISG15<jats:sup>\u2212\/\u2212<\/jats:sup> mice further supports a critical dual function of ISG15 in controlling chlamydial infection and modulating the resulting inflammatory responses.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013315","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T15:31:30Z","timestamp":1751988690000},"page":"e1013315","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Secreted ISG15 induced by Chlamydia trachomatis infection exerts immunomodulatory effects on IFN-\u03b3 defense and inflammation"],"prefix":"10.1371","volume":"21","author":[{"given":"Yongxia","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrun V.","family":"Stulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Komla","family":"Kessie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Vollmuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Torcellan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Peter","family":"Knobeloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Gasteiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4740-6991","authenticated-orcid":true,"given":"Thomas","family":"Rudel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"issue":"12","key":"ppat.1013315.ref001","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0143304","article-title":"Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting","volume":"10","author":"L Newman","year":"2015","journal-title":"PLoS One"},{"issue":"1","key":"ppat.1013315.ref002","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.fertnstert.2007.05.070","article-title":"Chlamydia trachomatis infection in women with secondary infertility","volume":"91","author":"A Malik","year":"2009","journal-title":"Fertil Steril"},{"issue":"6","key":"ppat.1013315.ref003","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1128\/JCM.38.6.2292-2296.2000","article-title":"Urogenital Chlamydia trachomatis serovars in men and women with a symptomatic or asymptomatic infection: an association with clinical manifestations?","volume":"38","author":"SA Morr\u00e9","year":"2000","journal-title":"J Clin Microbiol"},{"issue":"25","key":"ppat.1013315.ref004","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1056\/NEJMcp030542","article-title":"Clinical practice. 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