The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney.
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.
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Kritika
K
Ramani
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Abhishek V
AV
Garg
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Chetan V
CV
Jawale
Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
Heather R
http://orcid.org/0000-0002-1491-4212
HR
Conti
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Natasha
http://orcid.org/0000-0001-5765-1646
N
Whibley
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Edwin K
EK
Jackson
Vascular Medicine Institute, Dept. of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Sruti S
SS
Shiva
Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
William
W
Horne
Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Jay K
JK
Kolls
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Sarah L
SL
Gaffen
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Partha S
PS
Biswas
D000818:Animals; D015153:Blotting, Western; D002177:Candidiasis / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000276:immunology*; D016234:Kallikrein-Kinin System / Q000276:immunology*; D007674:Kidney Diseases / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
D020381:Interleukin-17