ABSTRACT
Human fungal pathogens such as the dimorphic Candida albicans or the yeast-like Candida glabrata can cause systemic candidiasis of high mortality in immunocompromised individuals. Innate immune cells such as dendritic cells and macrophages establish the first line of defense against microbial pathogens and largely determine the outcome of infections. Among other cytokines, they produce type I IFNs (IFNs-I), which are important modulators of the host immune response. Whereas an IFN-I response is a hallmark immune response to bacteria and viruses, a function in fungal pathogenesis has remained unknown. In this study, we demonstrate a novel mechanism mediating a strong IFN-ß response in mouse conventional dendritic cells challenged by Candida spp., subsequently orchestrating IFN-α/ß receptor 1-dependent intracellular STAT1 activation and IFN regulatory factor (IRF) 7 expression. Interestingly, the initial IFN-ß release bypasses the TLR 4 and TLR2, the TLR adaptor Toll/IL-1R domain-containing adapter-inducing IFN-ß and the ß-glucan/phagocytic receptors dectin-1 and CD11b. Notably, Candida-induced IFN-ß release is strongly impaired by Src and Syk family kinase inhibitors and strictly requires completion of phagocytosis as well as phagosomal maturation. Strikingly, TLR7, MyD88, and IRF1 are essential for IFN-ß signaling. Furthermore, in a mouse model of disseminated candidiasis we show that IFN-I signaling promotes persistence of C. glabrata in the host. Our data uncover for the first time a pivotal role for endosomal TLR7 signaling in fungal pathogen recognition and highlight the importance of IFNs-I in modulating the host immune response to C. glabrata.
Subject(s)
Candida albicans/immunology , Candida glabrata/immunology , Dendritic Cells/immunology , Interferon Type I/physiology , Interferon-beta/physiology , Phagosomes/immunology , Signal Transduction/immunology , Toll-Like Receptor 7/physiology , Animals , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Bone Marrow Cells/microbiology , Cells, Cultured , Coculture Techniques , Dendritic Cells/metabolism , Dendritic Cells/microbiology , Humans , Interferon-beta/metabolism , Macrophages/immunology , Macrophages/metabolism , Macrophages/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Phagosomes/metabolism , Phagosomes/microbiology , Toll-Like Receptor 7/deficiency , Toll-Like Receptor 7/geneticsABSTRACT
The in vitro activities of 17 antifungal drugs against a panel of 20 dermatophytes comprising 6 different species were determined using a microdilution assay according to the NCCLS M38-P method with some modifications. Terbinafine was the most potent systemic drug while tolnaftate and amorolfine were the most active topical agents.
