Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

口咽念珠菌病(OPC)是一种机会性真菌感染，与 免疫缺陷，尤其是在T细胞室。白色念珠菌是一种共生菌 真菌是OPC的主要致病物种，其主要毒力特征是 形成入侵菌丝的能力。真菌的这种形态转变引发了 口腔上皮细胞(OECs)的“危险”反应，这是第一种类型的细胞 遇到这种微生物。在2009年，我们展示了一种有效的免疫反应 小鼠的粘膜念珠菌病需要细胞因子IL-17(IL-17A)的信号。这个 IL-17在IL-17R缺乏症患者中的重要性已得到证实。使用鼠标作为 模型生物体，我们证明了在幼稚的环境中(即，先天反应)，IL-17被 由两个天生的淋巴细胞亚群：Gd-T细胞和‘天然’Th17细胞(NTh17)所致。在召回中 (即适应性)反应，IL-17另外由传统的CD4Th17细胞产生， 这增强了先天反应，加速了真菌的清除。总的来说，IL-17 细胞包括“17型”免疫。无论来源如何，IL-17通过一种 IL-17RA和IL-17RC的异源二聚体，在基质细胞上高表达 和上皮室。OPC的启动事件是嗅鞘细胞暴露于C。 白念珠菌。然而，尚不清楚早期的上皮识别事件如何导致 激活17型反应，以及为什么这些反应只发生在对 菌丝。在一项里程碑式的发现中，第一合作者(Naglik博士)表明，危险反应 在OECs中被毒力因子Candidalysin激活，Candidalysin是第一个造孔肽 在任何人类真菌病原体中发现的毒素。念珠菌素只由菌丝分泌 并使OEC膜渗透。念珠菌素触发MAPK依赖 途径，导致细胞因子、趋化因子和抗菌肽上调 对OPC的免疫力是必不可少的。我们在这次续集中的首要目标是 深入定义宿主和病原体衍生因子的机制 协调有效的针对白色念珠菌的17型免疫。

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.