Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

17 型口腔念珠菌病免疫的宿主和真菌调节

• 批准号: 9397690
• 负责人: Sarah L Gaffen
• 金额: $ 54.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397690
• 关键词: Acquired Immunodeficiency Syndrome; Adrenal Cortex Hormones; Animal Model; Breathing; CCL20 gene; Candida albicans; Candidiasis; Cell Communication; Cell Compartmentation; Cell membrane; Cells; Chronic; Complex; Cytokine Signaling; Cytolysis; Data; Disease; Elderly; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Event; Exhibits; FOS gene; Family; Funding; Goals; Grant; Host Defense; Human; Hyphae; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Individual; Infant; Inflammation Mediators; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-17; Interleukin-6; Keratin; Lead; Link; Lymphocyte; MAP Kinase Gene; Microbe; Morphology; Mouth Diseases; Mus; Mycoses; Nature; Oral; Oral candidiasis; Oral mucous membrane structure; Pathogenicity; Pathway interactions; Peptides; Pharmaceutical Preparations; Recruitment Activity; Regulation; Reporting; Research; Role; Signal Transduction; Source; Symbiosis; System; T-Lymphocyte; Tissues; Toxin; Transgenic Mice; Transplant Recipients; Up-Regulation; Virulence; Virulence Factors; Virulent; asthmatic patient; cell type; chemotherapy; cytokine; defined contribution; experience; feeding; fungus; immune function; in vivo; mucosal vaccine; oropharyngeal thrush; pathogen; receptor; response; tool; trait; γδ T cells

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.

摘要 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)中的“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的重要性随后在患有IL-17R缺陷的人类中得到证实， 患有慢性粘膜念珠菌病的人。以小鼠为模型生物，我们 表明在幼稚的环境中(即先天反应)，IL-17是由两个先天的 淋巴细胞亚群：γδ-T细胞和“天然”Th17细胞(NTh17)。在调用中(即，自适应) 反应，IL-17是由传统的CD4+Th17细胞额外产生的，这增加了 加速真菌清除的先天反应。总的来说，IL-17+细胞包括 “17型”豁免权。无论来源如何，IL-17都通过一个普遍存在的受体(A)传递信号 IL-17RA和IL-17RC的杂二聚体)。在第一个资助期，我们展示了OEC 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- 13CRE转基因小鼠在嗅鞘细胞中有条件地缺失IL-17RA。 OPC的始动事件是嗅鞘细胞暴露于白色念珠菌。然而，它仍然 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对菌丝有反应。在一个里程碑式的发现中 最近在《自然》杂志上发表的一篇文章中，该合作者(Naglik博士)表明， 嗅鞘细胞被一种新发现的毒力因子--念珠菌素激活，第一个毛孔-- 在任何人类真菌病原体中发现的形成多肽毒素。念珠菌素是分泌的 特别是通过菌丝和渗透OEC膜。假丝酵母素引发一种 通过c-fos的MAPK依赖途径，导致细胞因子如 IL-1、β、IL-6和CCL20。我们的新数据显示：(1)念珠菌素激活嗅鞘细胞 通过表皮生长因子受体(EGFR)反应，(Ii)需要念珠菌素 在体内诱导天然淋巴细胞表达IL-17，以及(Iii)念珠菌素和IL-17 协同发出信号以增强OEC的激活。鉴于这些令人兴奋的观察，我们的 首要目标是了解寄主-和病原体- 衍生因子协调针对白色念珠菌的有效的17型免疫。我们的中央 假说认为念珠菌素通过诱导嗅鞘细胞产生炎症介质。 EGFR/c-fos危险反应通路，从而触发必要的先天适应性 输入17个回复。反过来，IL-17与假丝酵母素在嗅鞘细胞上协同信号， 其用于在前馈激活环路中放大宿主防御。