Abstract
The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of antifungal drug resistance and lack of vaccines against fungal pathogens. IL-17 is a key mediator of defense against candidiasis. The underlying mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms, particularly activation of neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner. 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 C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone. These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection.
Highlights
The commensal fungus Candida albicans causes several clinical conditions in immunocompromised individuals, including oropharyngeal candidiasis (OPC, thrush) and vaginal candidiasis [1]
Candida albicans is the causative agent of oropharyngeal candidiasis (OPC, thrush), dermal and vaginal candidiasis
The most severe C. albicans-induced disease is disseminated candidiasis, a frequent nosocomial infection associated with a high mortality rate
Summary
The commensal fungus Candida albicans causes several clinical conditions in immunocompromised individuals, including oropharyngeal candidiasis (OPC, thrush) and vaginal candidiasis [1]. The most severe Candida-induced disease is a systemic form of bloodstream candidiasis. Disseminated candidiasis is the fourth most common hospital acquired infection and is associated with a 40–60% mortality rate [2,3]. Intravascular catheters, abdominal surgery, prolonged use of antibiotics and immunosuppressive therapy are risk factors for this disease, and contribute to the concerning rise in the incidence of candidiasis [1]. Available antifungal medications are limited by drug-drug interactions, drug resistance, toxicity and high treatment costs. There is an unmet clinical need to develop alternative, safe and ideally inexpensive approaches to treat this fatal infection
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