Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

点击翻译按钮获取中文摘要

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 confirmed in humans with IL-17R-deficiencies. 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: gd-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 heterodimer of IL-17RA and IL-17RC, which is highly expressed on cells of the stromal and epithelial compartments. 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 the co-I (Dr. Naglik) showed that the danger response in OECs is activated by a virulence factor, Candidalysin, the first pore-forming peptide toxin identified in any human fungal pathogen. Candidalysin is secreted only by hyphae and permeabilizes OEC membranes. Candidalysin triggers a MAPK-dependent pathway, leading to upregulation of cytokines, chemokines and antimicrobial peptides that are essential for immunity to OPC. Our overarching goal in this continuation is to define in depth the mechanisms by which host-and pathogen-derived factors coordinate effective Type 17 immunity against C. albicans.