IL-17-epithelial cells interaction in organ damaging infections

ABSTRACT The di-morphic commensal fungus Candida albicans causes severe bloodstream infection known as disseminated candidiasis (candidiasis). Candidiasis is the 3rd most common nosocomial infection, with mortality rates ~40-60%. Currently, there are no approved vaccines to this or any other fungi. Following systemic infection, C. albicans hyphae invade and damage vital organs including kidney. Aggressive treatment with antifungal drugs is hampered by challenges in early diagnosis, development of drug resistance, and a poor mechanistic understanding of the renal protective immunity. In recent years, the proinflammatory cytokine Interleukin-17 (IL- 17) has emerged as a key player in antifungal defense. We discovered a surprising kidney tissue protective role of IL-17 in candidiasis. The renal tubular epithelial cells (RTECs) undergo increased apoptosis following hyphal invasion of the kidney. We demonstrate that RTECs undergo loss of mitochondrial membrane potential, increased mitoROS production and Caspase3 activation in candidiasis, a phenotype aggravated in the absence of IL-17RA signaling. Our preliminary data show that mice lacking IL-17 signaling in RTECs exhibit reduced renal expression of nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4) in candidiasis, which is critical to prevent activation of apoptotic pathways. The overall goal of this proposal is to determine the mechanisms of IL-17-mediated kidney tissue protection in candidiasis and ultimately to utilize this knowledge for the treatment of kidney damage. To that end, we will use RTEC-specific deletion of Ndufs4 to define the role for IL-17/Ndufs4 pathway in protecting RTECs from mitochondrial dysfunction and apoptosis (Aim 1). We will interrogate the cellular signaling events downstream of IL-17 signaling in regulation of Ndufs4 gene expression in mouse and human RTECs (Aim 2). Knowledge gained from these studies will advance our understanding on the tissue protective function of IL-17 in infectious settings. Our long-term goal is to reduce the morbidity and mortality associated with this devastating organ damaging infection.