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

基本信息

批准号：
10551422
负责人：
Sarah L Gaffen
金额：
$ 59.74万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551422
关键词：
Acquired Immunodeficiency Syndrome Adaptive Immune System Adrenal Cortex Hormones Animal Model Antifungal Agents Area Automobile Driving CCAAT-Enhancer-Binding Proteins Candida albicans Candidiasis Cell Communication Cell Compartmentation Cell Differentiation process Cell Proliferation Cell membrane Cells Client Cytokine Receptors Cytokine Signaling Data Data Set Elderly Epidermal Growth Factor Receptor Epithelial Epithelial Cells Event Family Family member Funding Genetic Transcription Goals Grant Homeostasis Host Defense Human Hyphae Immune Immune response Immune system Immunity Immunology Immunosuppressive Agents Individual Infant Infection Inhalation Interleukin-1 Interleukin-17 Laboratories Lead Light Location Lymphocyte MAP Kinase Gene Mediating Microbe Molecular Morphology Mouth Diseases Mucosal Immunity Mucous Membrane Mus Mycoses NF-kappa B Neutrophil Infiltration Oral Oral candidiasis Oral cavity Oral mucous membrane structure Pathway interactions Peptides Pharmaceutical Preparations Production Property RNA Stability RNA-Binding Proteins Regulation Reporting Research STAT3 gene Signal Pathway Signal Transduction Site Source Stromal Cells System T cell response T-Lymphocyte TIS11 protein Tissues Toxin Transcript Translations Transplant Recipients Up-Regulation Virulence Virulence Factors Work antimicrobial peptide asthmatic patient cell type chemokine chemotherapy cytokine draining lymph node epithelial repair fungus immune function interest interleukin-22 interleukin-23 mucosal vaccine oral cavity epithelium oral immunity oral infection oral pathogen oral tissue oropharyngeal thrush p38 Mitogen Activated Protein Kinase pathogen pathogenic fungus response single-cell RNA sequencing stem tissue regeneration tissue repair trait transcription factor

项目摘要

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.

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。在患有IL-17R缺乏的人类中，IL-17的重要性得到了证实。将小鼠用作模型有机体，我们表明，在幼稚的环境（即先天反应）中，进行IL-17 由两个先天淋巴细胞细胞亚群：GD-T和“天然” Th17细胞（NTH17）。在召回中（即自适应）反应，IL-17是由常规CD4+TH17细胞制成的这增加了对加速真菌清除的天生反应。共同，IL-17+ 细胞包含“ 17型”免疫力。不管来源如何，IL-17通过 IL-17RA和IL-17RC的异二聚体，在基质的细胞上高度表达和上皮室。 OPC中的开始事件是将OEC暴露于C中。白色唱片。但是，尚不清楚早期上皮识别事件如何导致 17型反应的激活，以及为什么这些响应仅出于响应菌丝。在具有里程碑意义的发现中，co-i（纳格里克博士）表明危险反应在OEC中，通过病毒因子念珠菌素激活，第一个形成孔的肽毒素在任何人类真菌病原体中都鉴定出来。念珠菌素仅由菌丝分泌并渗透OEC膜。念珠菌素会触发MAPK依赖性途径，导致细胞因子，趋化因子和抗菌胡椒的上调对OPC的免疫力至关重要。我们在这个延续中的总体目标是深入定义宿主和病原体衍生因素的机制协调对白色念珠菌的有效17型免疫。