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.

Candida albicans 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 Candida 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 C. albicans 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 C. albicans. 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.