Differential requirements of IL-17 family cytokines in host defense against oral candidiasis (CCR6P.272)
2014
Antibodies against IL-17A and IL-17RA are in clinical trials for autoimmunity. Mutations in IL-17 signaling genes (IL17RA, IL17F, ACT1) cause susceptibility to mucocutaneous infection by the fungus Candida albicans. IL-17A, IL-17F and IL-17C all signal via IL-17RA, but their individual roles in controlling candidiasis are poorly defined. Accordingly, in vivo Ab neutralization of cytokines or knockout mice were evaluated in a model of oropharyngeal candidiasis (OPC). Following C. albicans exposure, tongue fungal burden after 4 d, weight change and target gene expression were assessed. Anti-IL-17A-treated mice showed modestly impaired clearance compared to WT at d4, whereas α-IL-17F-treated mice were not affected. However, IL-17RA-/- and Act1-/- mice were far more susceptible to OPC than α-IL-17A treated mice at 4 and 14 d, indicating contributions to immunity beyond IL-17A. Susceptibility was associated with reduced expression of IL-17-regulated genes encoding chemokines and defensins. In contrast to α-IL-17A-treated mice, IL-17A-/- mice showed no significant susceptibility to OPC. This discrepancy was not explained by contributions from IL-17F or IL-17C, because α-IL-17F-treated IL-17A-/- mice and IL-17C-/- mice cleared the infection as well as WT mice. The increased susceptibility of IL-17RA-/- and Act1-/- mice vs. those lacking specific cytokines implies compensation between IL-17 family cytokines and possibly additional antifungal effectors. Funded by Novartis and NIDCR.
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