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.

抽象的 口咽念珠菌病（OPC）是一种机会性真菌感染 免疫缺陷，特别是在T细胞室中。白色念珠菌是一个共同的 真菌是OPC的主要致病物种，其关键病毒特征是 能够形成侵入性菌丝。真菌触发的这种形态过渡 口腔上皮细胞（OEC）中的“危险”反应，这是第一个细胞类型 遇到这个微生物。在2009年，我们表明对 小鼠中的粘膜念珠菌病需要细胞因子IL-17（IL-17A）信号传导。 IL-17的重要性随后在患有IL-17R缺乏的人类中得到了证实， 经历了慢性粘膜念珠菌病。使用小鼠作为模型生物，我们 表明，在幼稚的环境（即先天性的反应）中，IL-17由两个先天性做出 淋巴细胞细胞子集：γδ-T和“天然” Th17细胞（NTH17）。在召回中（即自适应） 响应，IL-17还由常规CD4+TH17细胞制成，增强 对加速真菌清除的天生反应。总体而言，IL-17+细胞包含 “ 17型”免疫力。不管来源如何，IL-17通过无处不在的接收器信号（a IL-17RA和IL-17RC的异二聚体）。在第一个资金期间，我们证明了OEC 是关键的IL-17响应细胞类型，我们通过创建新的角蛋白 - 13CRE转基因小鼠在OEC中有条件删除IL-17RA。 OPC中的开始事件是OEC暴露于白色念珠菌。但是，它仍然是 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仅是响应菌丝的原因。在地标发现 最近在自然界报道的是，Co-I（Naglik博士）表明，舞者的反应 OEC被新发现的病毒因子念珠菌素激活，这是第一个孔隙 在任何人类真菌病原体中鉴定出肽毒素。念珠菌是分泌的 candidalysin触发a MAPK依赖性途径通过C-Fos，导致细胞因子的上调，例如 IL-1β，IL-6和CCL20。我们的新数据表明（i）念珠菌素激活OEC 通过表皮生长因子受体（EGFR）的反应，（ii）念珠菌素需要 在体内诱导先天淋巴细胞中的IL-17表达，以及（iii）念珠菌素和IL-17 信号合作以增强OEC激活。考虑到这些令人兴奋的观察，我们 总体目标是了解宿主和病原体的机制 派生因子协调有效的17型免疫力对白色念珠菌。我们的中心 假设是念珠菌素通过 egfr/c-fos危险响应途径，从而触发了必要的先天和适应性 17型响应。反过来，IL-17与OEC上的candidalysin合作发出信号， 它可以在进率向前的激活环中扩增宿主防御。