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.

Grant Number: 5R21AI181831-02
NIH Institute/Center: NIH
Principal Investigator: Partha Biswas