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A core characteristic of VVC is the interplay between\u00a0Candida\u00a0albicans pathogenicity and dysregulated innate immune responses. While these inflammatory responses generally underlie VVC severity, epithelial type I interferon (IFN) responses have been associated with improved epithelial resistance to infection and dampened downstream neutrophil activation. Yet, the role of interferon-stimulated genes (ISGs) in epithelial resistance to C. albicans infection remains unclear. Here, we investigated the threshold for mounting type I IFN responses in A-431 vulvovaginal epithelial cells (VECs), and the role of interferon-stimulated gene 15 (ISG15) in epithelial resistance and inflammation. We found that increasing C. albicans burdens corresponded to increasing epithelial cytotoxicity and the release of neutrophil chemoattractant IL-8. Further, expression of IFNB1 and ISGs, specifically ISG15 and MX2, was induced at fungal burdens, before the induction of significant cytotoxicity at later time points. We observed intracellular ISG15 accumulation following\u00a0C. albicans infection, yet detected reduced unconjugated intracellular ISG15, suggesting its conjugation to other proteins. Mechanistically, we show that ISG15 silencing reduced epithelial cytotoxicity and IL-8 responses to C. albicans infection. Concurrently, a C. albicans infection-specific downregulation of the gene encoding the cell death regulator Z-DNA binding protein 1 (ZBP1) was observed. Accordingly, ZBP1 silencing, similar to ISG15, exhibited reduced tissue damage and IL-8 responses. Collectively, our data suggest that ISG15, expressed by VECs upon C. albicans infection, may exert negative feedback on epithelial resistance to infection induced by type I IFNs.<\/jats:p>","DOI":"10.1093\/femsml\/uqag024","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T23:29:33Z","timestamp":1783380573000},"source":"Crossref","is-referenced-by-count":0,"title":["Interferon-stimulated gene 15 expression negatively regulates resistance to\n                    <i>Candida albicans<\/i>\n                    infection in vulvovaginal epithelial cells"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2879-462X","authenticated-orcid":false,"given":"J\u00f6rdis V","family":"Schuchardt","sequence":"first","affiliation":[{"name":"Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans-Kn\u00f6ll-Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11a, 07745 Jena, Thuringia ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Urtecho\u00a0Valverde","sequence":"additional","affiliation":[{"name":"Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans-Kn\u00f6ll-Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11a, 07745 Jena, Thuringia ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9655-0984","authenticated-orcid":false,"given":"Beatriz","family":"Crist\u00f3v\u00e3o","sequence":"additional","affiliation":[{"name":"Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans-Kn\u00f6ll-Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11a, 07745 Jena, Thuringia ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1991-9634","authenticated-orcid":false,"given":"Marina","family":"Pekmezovi\u0107","sequence":"additional","affiliation":[{"name":"Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans-Kn\u00f6ll-Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11a, 07745 Jena, Thuringia ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7020-5613","authenticated-orcid":false,"given":"Raquel","family":"Alonso-Roman","sequence":"additional","affiliation":[{"name":"Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans-Kn\u00f6ll-Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11a, 07745 Jena, Thuringia ,","place":["Germany"]},{"name":"Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans-Kn\u00f6ll-Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11a, 07745 Jena, Thuringia ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-7522","authenticated-orcid":false,"given":"Mark S","family":"Gresnigt","sequence":"additional","affiliation":[{"name":"Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans-Kn\u00f6ll-Institute (Leibniz-HKI) , Beutenbergstra\u00dfe 11a, 07745 Jena, Thuringia ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"2026071309165083200_bib1","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1128\/cmr.00076-09","article-title":"Candida infections of the genitourinary 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