Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

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Abstract Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection associated with immune deficiency, particularly in the T cell compartment. C. albicans is a commensal fungus that is the dominant causative species of OPC, and its key virulence trait is the ability to form invasive hyphae. This morphologic transition in the fungus triggers `danger' responses in oral epithelial cells (OECs), which are the first cell types to encounter this microbe. In 2009, we showed that an effective immune response to mucosal candidiasis in mice requires signaling by the cytokine IL-17 (IL-17A). The importance of IL-17 was subsequently confirmed in humans with IL-17R-deficiencies, who experience chronic mucosal candidiasis. Using mice as a model organism, we showed that in naïve settings (i.e., innate responses), IL-17 is made by two innate lymphocyte cell subsets: γδ-T and `natural' Th17 cells (nTh17). In recall (i.e., adaptive) responses, IL-17 is additionally made by conventional CD4+Th17 cells, which augment the innate response to accelerate fungal clearance. Collectively, IL-17+ cells comprise “Type 17” immunity. Regardless of source, IL-17 signals through a ubiquitous receptor (a heterodimer of IL-17RA and IL-17RC). In the first funding period, we showed that OECs are the key IL-17-responsive cell type, which we achieved by creating a new Keratin- 13CRE transgenic mouse that deletes IL-17RA conditionally in OECs. The initiating event in OPC is exposure of OECs to C. albicans. However, it remains unclear how early epithelial recognition events lead to activation of Type 17 responses, and why these responses occur only in response to hyphae. In a landmark discovery recently reported in Nature, the co-I (Dr. Naglik) showed that the danger response in OECs is activated by a newly-discovered virulence factor, Candidalysin, the first pore- forming peptide toxin identified in any human fungal pathogen. Candidalysin is secreted specifically by hyphae and permeabilizes OEC membranes. Candidalysin triggers a MAPK-dependent pathway through c-fos, leading to upregulation of cytokines such as IL-1β, IL-6 and CCL20. Our new data reveal that (i) Candidalysin activates OEC responses via the epidermal growth factor receptor (EGFR), (ii) Candidalysin is required to induce IL-17 expression in innate lymphocytes in vivo, and (iii) Candidalysin and IL-17 signal cooperatively to enhance OEC activation. Given these exciting observations, our overarching goal is to understand the mechanisms by which host-and pathogen- derived factors coordinate effective Type 17 immunity against C. albicans. Our central hypothesis is that Candidalysin induces inflammatory mediators in OECs through an EGFR/c-fos danger response pathway, thereby triggering essential innate and adaptive Type 17 responses. In turn, IL-17 signals cooperatively with Candidalysin on OECs, which serves to amplify host defense in a feed-forward activation loop.