Card9 deficiency exacerbates vulvovaginal candidiasis by impairing the IL-17 production and vaginal epithelial barrier.

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-/- 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 γδ 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.