Biphasic Regulation of Epithelial Antimicrobial Peptides During Candida albicans Vaginal Infection: Distinct Contributions of NLRP3/IL-1β and IL-17RA Pathways to β-Defensin-1 and -3 Expression

<i>Candida albicans</i> is the primary agent of acute vulvovaginal candidiasis (VVC) and its recurrent form (RVVC). Local innate immunity contributes to both defense and pathogenesis during vaginal <i>Candida</i> infection, where epithelial β-defensins (BD) constitute key components of the mucosal barrier. We previously reported that epithelial BD-1 expression is dynamically modulated during murine and human vaginitis, revealing strain-dependent and stimulus-specific regulation but leaving the host pathways involved unresolved. This study functionally defines the contribution of key immune pathways to epithelial antimicrobial peptide regulation. Using a murine model of VVC and the virulent <i>C. albicans</i> strain SC5314, we aimed to evaluate the immune signaling pathways governing the temporal regulation of epithelial BD-1 and BD-3 expression during vaginal infection. In wild-type mice, both defensins displayed a biphasic pattern: early induction followed by attenuation as infection progressed. Genetic loss-of-function approaches revealed that NLRP3/IL-1β signaling is required for early BD-1 induction, whereas IL-17RA signaling preferentially supports sustained BD-3 expression. Together, these findings establish a causal and temporal link between host immune signaling and epithelial defensin regulation and reveal a transient subversion of mucosal defenses by <i>C. albicans</i>. This work advances understanding of epithelial innate immunity, defining distinct temporal programs for BD-1 and BD-3 and identifying NLRP3/IL-1β and IL-17RA signaling as key pathways shaping mucosal defensin expression.