Mechanisms of IL-17 Mediated Host Defense in the Kidney

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 DESCRIPTION (provided by applicant): Candida albicans is a commensal fungus that resides in the oral cavity and gut mucosa. Normally, healthy humans efficiently control the colonization of Candida. However, in certain conditions such as solid organ and hematopoietic stem cell transplantation, receipt of immunosuppressive therapy, cancer, premature birth or indwelling catheterization, Candida albicans can disseminate and cause life-threatening systemic disease. In fact, disseminated candidiasis is the 4th most common nosocomial infection, with fatality rates up to 40-60%. The lack of effective vaccines and development of drug resistance act as major constraints in successfully treating these patients. Therefore, there is a serious unmet clinical need to develop better therapeutic and prophylactic strategies to combat these fatal infections. During disseminated infection, Candida hyphae invade target organs, particularly kidney and liver. Death from candidemia results from renal insufficiency in a substantial number of patients. While the contribution of mucosal immune system in anti-Candida host defense has been well studied in recent years, the role of local immunity in target organs, particularly the kidney, is largely overlooked. The cytokine IL-17 has emerged as a key mediator of host defense against Candida species. Both humans and experimental mouse models deficient in IL-17 pathways such as the IL-17 receptor A (IL-17RA) are susceptible to disseminated candidiasis. Our preliminary data show that IL-17RA signaling in non-hematopoietic cells is required for renal defense against systemic Candida infection. Nevertheless, the underlying mechanisms of IL-17-mediated host defense against systemic candidiasis particularly in the kidney are not known. Interestingly, we have discovered an unexpected role for IL-17 in inducing the Kallikrein-Kinin System (KKS) in kidney following candidemia. We also show that overexpression of Klk1 protects IL-17RA-/- mice from candidemia. Kallikreins are serine proteases that cleave kininogens to form bradykinin. The KKS system is known to be involved in renal protection against both acute and chronic kidney injury, but almost no connections of the KKS to candidiasis have been previously reported. The overall goal of this grant application is to determine the underlying mechanisms of IL-17-Klk1 mediated immunity during systemic candidiasis and ultimately to exploit this knowledge for therapeutic benefit. To that end, we will use a series of renal cell type specific gene-targeted mice, global Klk1 and bradykinin receptor-deficient mice and bradykinin receptor agonists to define mechanisms of IL-17-driven renal protection against candidemia (Aim 1). Knowledge gained from these studies will be used in pre-clinical studies to evaluate the therapeutic efficacy of targeting IL-17- KKS axis in kidney specific anti-fungal immunity (Aim 2). Our long term goal is to reduce the morbidity and mortality associated with this devastating hospital acquired infection.