{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:37:04Z","timestamp":1776436624212,"version":"3.51.2"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82030095"],"award-info":[{"award-number":["82030095"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82304044"],"award-info":[{"award-number":["82304044"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007937","name":"Peking University","doi-asserted-by":"publisher","award":["2024CX04"],"award-info":[{"award-number":["2024CX04"]}],"id":[{"id":"10.13039\/501100007937","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007937","name":"Peking University","doi-asserted-by":"publisher","award":["2023SF02"],"award-info":[{"award-number":["2023SF02"]}],"id":[{"id":"10.13039\/501100007937","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005090","name":"Beijing Nova Program","doi-asserted-by":"publisher","award":["20230484339"],"award-info":[{"award-number":["20230484339"]}],"id":[{"id":"10.13039\/501100005090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Vulvovaginal candidiasis (VVC) is an inflammation caused by Candida albicans with a higher recurrence rate in individuals deficient in Card9. This study aimed to elucidate the mechanisms underlying this increased susceptibility. Estrogen-treated Card9\u2212\/\u2212 mice infected with C. albicans were used to model Card9 deficiency-related VVC. Our findings indicate that Card9 deficiency leads to a reduction in Th17 cells, interleukin (IL)-17-producing \u03b3\u03b4 T cells, and IL-17A secretion, weakens epithelial tight junctions, and reduces antimicrobial peptide secretion, leading to persistent fungal invasion. This persistent invasion results in excessive neutrophil recruitment and activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) and absent in melanoma 2 inflammasomes (AIM2), causing mucosal damage. In conclusion, Card9 deficiency compromises the vaginal epithelial barrier, prolongs C. albicans infection, and increases inflammation, highlighting the critical role of Card9 in maintaining immune function of vaginal mucosa.<\/jats:p>","DOI":"10.1093\/mmy\/myaf026","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T09:57:17Z","timestamp":1742723837000},"source":"Crossref","is-referenced-by-count":4,"title":["Card9 deficiency exacerbates vulvovaginal candidiasis by impairing the IL-17 production and vaginal epithelial barrier"],"prefix":"10.1093","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0695-9955","authenticated-orcid":false,"given":"Wenjie","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Dermatology and Venerology, Peking University First Hospital , Beijing 100034 ,","place":["China"]},{"name":"Research Center for Medical Mycology, Peking University , Beijing 100034 ,","place":["China"]},{"name":"Beijing Key Laboratory of Molecular Diagnosis on Dermatoses , Beijing 100034 ,","place":["China"]},{"name":"National Clinical Research Center for Skin and Immune Diseases , Beijing 100034 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1644-6942","authenticated-orcid":false,"given":"Yinggai","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venerology, Peking University First Hospital , Beijing 100034 ,","place":["China"]},{"name":"Research Center for Medical Mycology, Peking University , Beijing 100034 ,","place":["China"]},{"name":"Beijing Key Laboratory of Molecular Diagnosis on Dermatoses , Beijing 100034 ,","place":["China"]},{"name":"National Clinical Research Center for Skin and Immune Diseases , Beijing 100034 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruojun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venerology, Peking University First Hospital , Beijing 100034 ,","place":["China"]},{"name":"Research Center for Medical Mycology, Peking University , Beijing 100034 ,","place":["China"]},{"name":"Beijing Key Laboratory of Molecular Diagnosis on Dermatoses , Beijing 100034 ,","place":["China"]},{"name":"National Clinical Research Center for Skin and Immune Diseases , Beijing 100034 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venerology, Peking University First Hospital , Beijing 100034 ,","place":["China"]},{"name":"Research Center for Medical Mycology, Peking University , Beijing 100034 ,","place":["China"]},{"name":"Beijing Key Laboratory of Molecular Diagnosis on Dermatoses , Beijing 100034 ,","place":["China"]},{"name":"National Clinical Research Center for Skin and Immune Diseases , Beijing 100034 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruoyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venerology, Peking University First Hospital , Beijing 100034 ,","place":["China"]},{"name":"Research Center for Medical Mycology, Peking University , Beijing 100034 ,","place":["China"]},{"name":"Beijing Key Laboratory of Molecular Diagnosis on Dermatoses , Beijing 100034 ,","place":["China"]},{"name":"National Clinical Research Center for Skin and Immune Diseases , Beijing 100034 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venerology, Peking University First Hospital , Beijing 100034 ,","place":["China"]},{"name":"Research Center for Medical Mycology, Peking University , Beijing 100034 ,","place":["China"]},{"name":"Beijing Key Laboratory of Molecular Diagnosis on Dermatoses , Beijing 100034 ,","place":["China"]},{"name":"National Clinical Research Center for Skin and Immune Diseases , Beijing 100034 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"issue":"6","key":"2025040415303628300_bib1","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1111\/MYC.13248","article-title":"Guideline: vulvovaginal candidosis (AWMF 015\/072, level S2k)","volume":"64","author":"Farr","year":"2021","journal-title":"Mycoses"},{"issue":"6","key":"2025040415303628300_bib2","doi-asserted-by":"publisher","first-page":"905","DOI":"10.3109\/1040841X.2015.1091805","article-title":"Vulvovaginal candidiasis: epidemiology, microbiology and risk factors","volume":"42","author":"Gon\u00e7alves","year":"2016","journal-title":"Crit Rev Microbiol."},{"issue":"2","key":"2025040415303628300_bib3","doi-asserted-by":"publisher","first-page":"144","DOI":"10.3390\/MICROORGANISMS8020144","article-title":"Recurrent vulvovaginal candidiasis: an immunological perspective","volume":"8","author":"Rosati","year":"2020","journal-title":"Microorganisms"},{"key":"2025040415303628300_bib4","doi-asserted-by":"publisher","first-page":"880879","DOI":"10.3389\/FIMMU.2022.880879","article-title":"CARD9 signaling, inflammation, and diseases","volume":"13","author":"Liu","year":"2022","journal-title":"Front Immunol"},{"issue":"6","key":"2025040415303628300_bib5","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1007\/S10875-018-0539-2","article-title":"Inherited CARD9 deficiency: invasive disease caused by ascomycete fungi in previously healthy children and adults","volume":"38","author":"Corvilain","year":"2018","journal-title":"J Clin Immunol."},{"issue":"4","key":"2025040415303628300_bib6","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/MYC.13556","article-title":"Challenges towards management of CARD9-deficient patients with phaeohyphomycosis: A case report and case series study","volume":"66","author":"Zhang","year":"2023","journal-title":"Mycoses"},{"issue":"18","key":"2025040415303628300_bib7","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1056\/NEJMOA0810719","article-title":"A homozygous CARD9 mutation in a family with susceptibility to fungal infections","volume":"361","author":"Glocker","year":"2009","journal-title":"N Engl J Med."},{"key":"2025040415303628300_bib8","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.3389\/FMICB.2021.692491\/BIBTEX","article-title":"It takes two to tango: how a dysregulation of the innate immunity, coupled with Candida virulence, triggers VVC onset","volume":"12","author":"Ardizzoni","year":"2021","journal-title":"Front Microbiol."},{"issue":"3","key":"2025040415303628300_bib9","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/J.JACI.2013.09.033","article-title":"CARD9 mutations linked to subcutaneous phaeohyphomycosis and TH17 cell deficiencies","volume":"133","author":"Wang","year":"2014","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"2025040415303628300_bib10","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1007\/S10875-020-00909-0","article-title":"Primary cutaneous aspergillosis in a patient with CARD9 deficiency and Aspergillus susceptibility of Card9 knockout mice","volume":"41","author":"Zhang","year":"2021","journal-title":"J Clin Immunol."},{"issue":"2","key":"2025040415303628300_bib11","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1007\/S10875-021-01173-6","article-title":"CARD9 expression pattern, gene dosage, and immunodeficiency phenotype revisited","volume":"42","author":"Goel","year":"2022","journal-title":"J Clin Immunol."},{"issue":"6","key":"2025040415303628300_bib12","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1038\/NI1460","article-title":"Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17","volume":"8","author":"LeibundGut-Landmann","year":"2007","journal-title":"Nat Immunol"},{"issue":"11","key":"2025040415303628300_bib13","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1016\/J.CMI.2022.06.031","article-title":"Main human inborn errors of immunity leading to fungal infections","volume":"28","author":"Cifaldi","year":"2022","journal-title":"Clin Microbiol Infect"},{"issue":"9\u201310","key":"2025040415303628300_bib14","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1007\/S11046-016-0029-0","article-title":"Impairment of immune response against dematiaceous fungi in Card9 knockout mice","volume":"181","author":"Wu","year":"2016","journal-title":"Mycopathologia"},{"issue":"4","key":"2025040415303628300_bib15","doi-asserted-by":"publisher","first-page":"e01608","DOI":"10.1128\/MBIO.01608-21","article-title":"Signaling through Syk or CARD9 mediates species-specific anti- Candida protection in bone marrow chimeric mice","volume":"12","author":"Zajta","year":"2021","journal-title":"mBio"},{"issue":"17","key":"2025040415303628300_bib16","doi-asserted-by":"publisher","first-page":"4070","DOI":"10.3390\/ijms20174070","article-title":"Antagonistic effects of IL-4 on IL-17A-mediated enhancement of epidermal tight junction function","volume":"20","author":"Brewer","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"4","key":"2025040415303628300_bib17","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/J.IMMUNI.2015.09.003","article-title":"Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability","volume":"43","author":"Lee","year":"2015","journal-title":"Immunity"},{"issue":"5","key":"2025040415303628300_bib18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41419-022-04938-y","article-title":"Card9 protects sepsis by regulating Ripk2-mediated activation of NLRP3 inflammasome in macrophages","volume":"13","author":"Xu","year":"2022","journal-title":"Cell Death Dis"},{"issue":"2","key":"2025040415303628300_bib19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/MBIO.00182-15","article-title":"Transcriptomic analysis of vulvovaginal candidiasis identifies a role for the NLRP3 inflammasome","volume":"6","author":"Bruno","year":"2015","journal-title":"mBio"},{"issue":"1","key":"2025040415303628300_bib20","doi-asserted-by":"publisher","first-page":"17877","DOI":"10.1038\/S41598-017-17649-8","article-title":"NLRP3 inflammasome is a key player in human vulvovaginal disease caused by Candida albicans","volume":"7","author":"Roselletti","year":"2017","journal-title":"Sci Rep"},{"issue":"2","key":"2025040415303628300_bib21","doi-asserted-by":"publisher","first-page":"54","DOI":"10.3390\/PATHOGENS8020054","article-title":"Interleukin-17 in antifungal immunity","volume":"8","author":"Sparber","year":"2019","journal-title":"Pathogens"},{"issue":"3","key":"2025040415303628300_bib22","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/MI.2017.97","article-title":"Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation","volume":"11","author":"Li","year":"2018","journal-title":"Mucosal Immunol"},{"issue":"1","key":"2025040415303628300_bib23","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1095\/BIOLREPROD.110.090423","article-title":"Structure and function of intercellular junctions in human cervical and vaginal mucosal epithelia","volume":"85","author":"Blaskewicz","year":"2011","journal-title":"Biol Reprod"},{"issue":"5","key":"2025040415303628300_bib24","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1007\/S12551-019-00582-7","article-title":"The mechanobiology of tight junctions","volume":"11","author":"Citi","year":"2019","journal-title":"Biophys Rev"},{"issue":"8","key":"2025040415303628300_bib25","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/J.CMI.2016.05.016","article-title":"New clinical phenotypes of fungal infections in special hosts","volume":"22","author":"Pilmis","year":"2016","journal-title":"Clin Microbiol Infect"},{"issue":"6","key":"2025040415303628300_bib26","doi-asserted-by":"publisher","first-page":"434","DOI":"10.3390\/JOF10060434","article-title":"Card9 broadly regulates host immunity against experimental pulmonary Cryptococcus neoformans 52D infection","volume":"10","author":"Angers","year":"2024","journal-title":"J Fungi (Basel, Switzerland)"},{"issue":"2","key":"2025040415303628300_bib27","doi-asserted-by":"publisher","first-page":"e00211","DOI":"10.1128\/MBIO.00211-17","article-title":"Vaginal heparan sulfate linked to neutrophil dysfunction in the acute inflammatory response associated with experimental vulvovaginal candidiasis","volume":"8","author":"Yano","year":"2017","journal-title":"mBio"},{"key":"2025040415303628300_bib28","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1146\/ANNUREV-IMMUNOL-081022-021207","article-title":"Structural mechanisms of NLRP3 inflammasome assembly and activation","volume":"41","author":"Fu","year":"2023","journal-title":"Annu Rev Immunol."},{"issue":"3","key":"2025040415303628300_bib29","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1128\/IAI.01335-13","article-title":"The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections","volume":"82","author":"Bishu","year":"2014","journal-title":"Infect Immun."},{"issue":"1","key":"2025040415303628300_bib30","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/S41392-023-01620-3","article-title":"The IL-17 family in diseases: from bench to bedside","volume":"8","author":"Huangfu","year":"2023","journal-title":"Signal Transduct Target Ther"},{"issue":"3","key":"2025040415303628300_bib31","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/J.IMMUNI.2018.08.024","article-title":"SYK-CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer","volume":"49","author":"Malik","year":"2018","journal-title":"Immunity"},{"issue":"10","key":"2025040415303628300_bib32","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.1016\/J.CHOM.2023.08.016","article-title":"I\u03baB\u03b6 is an essential mediator of immunity to oropharyngeal candidiasis","volume":"31","author":"Taylor","year":"2023","journal-title":"Cell Host Microbe"},{"issue":"7","key":"2025040415303628300_bib33","doi-asserted-by":"publisher","first-page":"e22770","DOI":"10.1371\/JOURNAL.PONE.0022770","article-title":"Th17 cells and IL-17 in protective immunity to vaginal candidiasis","volume":"6","author":"Pietrella","year":"2011","journal-title":"PLoS One"},{"issue":"5","key":"2025040415303628300_bib34","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/J.CHOM.2016.10.001","article-title":"IL-17 receptor signaling in oral epithelial cells is critical for protection against oropharyngeal candidiasis","volume":"20","author":"Conti","year":"2016","journal-title":"Cell Host Microbe"},{"key":"2025040415303628300_bib35","doi-asserted-by":"publisher","first-page":"958480","DOI":"10.3389\/FROH.2022.958480","article-title":"Antimicrobial peptides: defending the mucosal epithelial barrier","volume":"3","author":"Johnstone","year":"2022","journal-title":"Front Oral Heal"},{"issue":"2","key":"2025040415303628300_bib36","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1128\/IAI.00861-13","article-title":"Vaginal epithelial cell-derived S100 alarmins induced by Candida albicans via pattern recognition receptor interactions are sufficient but not necessary for the acute neutrophil response during experimental vaginal candidiasis","volume":"82","author":"Yano","year":"2014","journal-title":"Infect Immun."},{"issue":"4","key":"2025040415303628300_bib37","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1016\/J.IMMUNI.2019.03.021","article-title":"The IL-17 family of cytokines in health and disease","volume":"50","author":"McGeachy","year":"2019","journal-title":"Immunity"}],"container-title":["Medical Mycology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/mmy\/advance-article-pdf\/doi\/10.1093\/mmy\/myaf026\/62521612\/myaf026.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mmy\/article-pdf\/63\/4\/myaf026\/62521612\/myaf026.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mmy\/article-pdf\/63\/4\/myaf026\/62521612\/myaf026.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T19:48:44Z","timestamp":1743796124000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mmy\/article\/doi\/10.1093\/mmy\/myaf026\/8090179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,21]]},"references-count":37,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4,2]]}},"URL":"https:\/\/doi.org\/10.1093\/mmy\/myaf026","relation":{},"ISSN":["1369-3786","1460-2709"],"issn-type":[{"value":"1369-3786","type":"print"},{"value":"1460-2709","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4]]},"published":{"date-parts":[[2025,3,21]]},"article-number":"myaf026"}}