Anti-fungal immune responses in the female reproductive tract - Project Summary Vulvovaginal candidiasis (VVC) represents a global health burden and an unmet clinical need. Vulvovaginal infection with the fungal commensal organism Candida albicans, unlike at other sites of infection, occurs in immunocompetent women. Remarkably, VVC has a prevalence of greater than 75%, and 15% of women experience recurrent infections, cumulatively resulting in significant cost burdens and decreases in quality of life. As there are currently no FDA-approved vaccines for any fungal pathogen, a greater understanding of the determinants of a protective anti-fungal immune response is a necessity. Many protective mechanisms have been identified for systemic, oral, and cutaneous C. albicans infection, but comparatively little is understood about tissue-specific protection at the vaginal mucosa. In murine models of VVC, mice are administered exogenous estrogen to render them susceptible to intravaginal infection with C. albicans, to which they are normally naïve. This is consistent with the increased susceptibility to VVC in humans, as infection is most common in post-pubescent and pre-menopausal women who have relatively higher estrogen levels. Type 3 cytokines (IL-17 family members and IL-22) are robustly induced in VVC and in non-vaginal sites are required for protective immune responses. However, in the case of VVC, the importance of type 3 cytokines has been controversial. Our lab and others have found that individual deletion of type 3 cytokines, their receptors/signaling adaptors, or inducers (Il17ra, Il22, Act1, or Il23p19) had little impact on VVC susceptibility. New data from our lab reveals that the combined actions of type 3 cytokines are required to protect from vaginal fungal infection, even without the induction of pseudoestrus. The proposed aims will determine the cellular and molecular basis for how type 3 cytokine signaling orchestrates immune control of VVC. Overall, this work will help address the substantial lack of knowledge regarding host factors required for protective immune responses against VVC and will help clarify a long-standing misconception in the field regarding the necessity of type 3 cytokines. Ultimately, these findings could help inform vaccine and therapeutic design for a prevalent and burdensome infection.
