Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

口咽念珠菌病是一种机会性真菌感染， 免疫缺陷，特别是在T细胞区室。C.白色念珠菌是一种 真菌是OPC的优势致病物种，其关键毒力性状是 形成侵入性菌丝的能力。真菌的这种形态转变 口腔上皮细胞（OECs）的“危险”反应，这是第一种细胞类型， 遇到这种微生物。在2009年，我们发现，有效的免疫反应， 小鼠的粘膜念珠菌病需要细胞因子IL-17（IL-17 A）的信号传导。的 IL-17的重要性在具有IL-17 R缺陷的人中得到证实。使用老鼠作为 模式生物，我们表明，在天真的设置（即，先天性反应），IL-17产生 由两个先天淋巴细胞亚群：gd-T和“天然”Th 17细胞（nTh 17）。In recall (i.e.,适应性）应答，IL-17另外由常规的CD 4 + Th 17细胞产生， 从而增强先天反应以加速真菌清除。总的来说，IL-17+ 细胞包含“17型”免疫。不管来源如何，IL-17通过一个信号传导途径， IL-17 RA和IL-17 RC的异二聚体，其在基质细胞上高度表达。 和上皮区室。OPC的起始事件是OEC暴露于C。 白色念珠菌然而，尚不清楚早期上皮识别事件如何导致 17型反应的激活，以及为什么这些反应只发生在对 菌丝在一个里程碑式的发现中，首席研究员（纳格里克博士）表明， 在嗅鞘细胞中，它被一种毒力因子，即第一个成孔肽， 人类真菌病原体中发现的毒素菌丝体只分泌放线菌素 并渗透OEC膜。枯草芽孢杆菌素触发MAPK依赖性 途径，导致细胞因子、趋化因子和抗菌肽的上调 对OPC免疫至关重要。我们在这方面的首要目标是 深入定义宿主和病原体衍生因子 协调有效的17型抗C免疫力。白色念珠菌

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.