The Kallikrein-kinin system: a novel player of IL-17-driven anti-Candida immune response in the Kidney

Abstract

Abstract Disseminated candidiasis is the fourth most common hospital acquired infection and is associated with a 40–60% mortality rate. During disseminated candidiasis, Candida albicans form invasive hyphae that damage kidney, leading to renal failure. Treatment of candidiasis is hindered by drug toxicity, the development of antifungal drug resistance and lack of vaccines against fungal pathogens. Previous studies have identified a key role of interleukin-17 (IL-17) in controlling systemic infection. The mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms. Here, we discovered an unanticipated role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in the infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Consequently, overexpression of Klk1 or treatment with bradykinin rescued IL-17RA−/− mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following disseminated infection. Moreover, combining a minimally effective dose of fluconazole with bradykinin strikingly improved survival compared to either drug alone. These findings have potential translational significance, as agonists of the KKS are in routine clinical use. Therefore, these results not only identify downstream mediators that could serve as novel drug targets, but could possibly be used to guide decisions on whether targeting these mediators could be a useful therapeutic option in conjunction with current antifungal drugs.