Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

摘要 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）中的“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-17A）的信号传导。的 IL-17的重要性随后在患有IL-17R缺陷的人中得到证实， 患有慢性粘膜念珠菌病。使用小鼠作为模型生物，我们 表明在幼稚的环境中（即，IL-17是由两种先天性免疫反应产生的。 淋巴细胞亚群：γ δ-T和"天然" Th17细胞（nTh17）。在回忆中（即，adaptive） IL-17另外由常规的CD4 + Th17细胞产生，其增强了免疫应答。 加速真菌清除的先天反应。总的来说，IL-17+细胞包含 "17型"免疫力。不管来源如何，IL-17通过普遍存在的受体（a IL-17 RA和IL-17 RC的异二聚体）。在第一个资助期，我们发现， 是关键的IL-17反应细胞类型，我们通过创造一种新的角蛋白- 在OEC中条件性缺失IL-17 RA的13CRE转基因小鼠。 OPC的起始事件是OEC暴露于C。白色念珠菌但委员会仍 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的反应中。在一个里程碑式的发现中 纳格利克博士最近在《自然》杂志上报道说， OECs被一种新发现的毒力因子激活，即第一个孔- 形成任何人类真菌病原体中鉴定的肽毒素。溶藻素分泌 特别是通过菌丝和透化OEC膜。溶藻素引发 通过c-fos的MAPK依赖性途径，导致细胞因子如 IL-1 β、IL-6和CCL20。我们的新数据表明，（i）拟南芥素激活OEC 通过表皮生长因子受体（EGFR）的反应，（ii）需要阿糖胞苷 诱导体内先天性淋巴细胞中IL-17的表达，和（iii）白藜芦醇和IL-17 协同信号传导以增强OEC活化。鉴于这些令人兴奋的观察结果，我们的 首要目标是了解宿主和病原体 衍生因子协调针对C的有效17型免疫。白色念珠菌我们的中央 一种假说认为，毛蕊花黄素诱导OEC中的炎症介质是通过 EGFR/c-fos危险反应通路，从而触发必要的先天和适应性 第17回答案反过来，IL-17与OECs上的毛蕊花黄素协同信号传导， 其用于在前馈激活环中放大宿主防御。

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.