IL-23/STAT3-Driven Oral Immune Responses to Candida albicans

IL-23/STAT3 驱动的针对白色念珠菌的口腔免疫反应

基本信息

批准号：
8977508
负责人：
Sarah L Gaffen
金额：
$ 38.5万
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：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977508
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Acute Address Adrenal Cortex Hormones Adverse effects Antibodies Antifungal Agents Antigen Receptors Autoimmunity Breathing C Type Lectin Receptors CD3 Antigens CD8B1 gene Candida Candida albicans Candidiasis Cell Proliferation Cells Chronic Mucocutaneous Candidiasis Clinical Trials Data Defect Defensins Development Disease Elderly Engineering Epithelial Cells Event Exhibits Family Flow Cytometry Frequencies Fungal Genes Gene Expression Profile Genes Goals Health Hematopoietic Human IgE Image Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes Immunosuppressive Agents In Situ Individual Infant Infection Interferon Type II Interleukin-17 Job&apos s Syndrome Kinetics Light Maintenance Mediating Microbe Mouse Strains Mouth Diseases Mucosal Immunity Mus Mutation Mycoses Natural Immunity Nature Opportunistic Infections Oral Oral candidiasis Oral cavity Oral mucous membrane structure Organism Pathway interactions Patients Pharmaceutical Preparations Phase Play Production Proteins Recurrence Regulation Reporter Reporting Research Resistance Role STAT3 gene Salivary Signal Pathway Signal Transduction Sjogren&apos s Syndrome Surface T-Lymphocyte Th1 Cells Tissues Transplant Recipients Vaccines adaptive immunity antimicrobial asthmatic patient cell type chemotherapy commensal microbes congenital immunodeficiency cytokine fungus immune function interleukin-23 mucosal vaccine novel oral cavity epithelium oral immunity oral infection oropharyngeal thrush pathogen receptor-mediated signaling response tool transcription factor two-photon

项目摘要

DESCRIPTION (provided by applicant): The oral cavity is the portal of entry for many infectious pathogens. Despite advances in the field of mucosal immunity, mechanisms of immunity in the oral mucosa remain surprisingly poorly understood. Candida albicans is a commensal fungus that commonly colonizes mucosal surfaces including the mouth. In healthy individuals, Candida is non-pathogenic. However, in immunodeficient patients, such as those with HIV/AIDS, Sjögren's syndrome, congenital immunodeficiency or those receiving chemotherapy, this microbe causes severe opportunistic infections of the oral cavity, known as "thrush" or oropharyngeal candidiasis (OPC). We recently discovered that immunity to OPC is highly dependent on IL-23, IL-17, and RORγt, overturning the long-held paradigm that immunity to Candida is mediated by Th1 cells and IFNγ. Our findings have been validated in in patients with rare immunodeficiency diseases that impact the IL-23/IL-17 pathway and who suffer from OPC and other forms of chronic mucocutaneous candidiasis (CMC). For example, Hyper-IgE/Job's Syndrome (HIES) is caused by mutations in STAT3, a transcription factor downstream of IL-23 and other cytokines. HIES patients have low levels of Th17 cells but not Th1 cells, and usually suffer recurrent OPC/CMC. Similarly, rare IL-17R-deficient families present with OPC and CMC. In this proposal, we will address several unanswered questions regarding oral immunity to Candida, emphasizing the IL-23/STAT3/IL- 17 pathway. It is clear there is a powerful innate response to Candida, but the nature of this cell type is unknown. Using new reporter mice, in Aim 1 we will determine the nature of the key IL-17-producing innate cell type that provides the early response to this organism. In Aim 2, we will evaluate mechanisms of immunity to OPC controlled by STAT3, particularly in oral epithelial cells. In Aim 3, we will evaluate the mechanisms by which IL-23 and STAT3 signaling regulate the adaptive anti-Candida Th17 response. Together, these studies will define the roles of STAT3, IL-23 signaling and IL-17 in the maintenance of oral mucosal immunity.

描述（由适用提供）：口腔是许多重要病原体的入口门户。尽管粘膜免疫学领域进步，但口腔粘膜中免疫学的机制仍然令人惊讶地了解。白色念珠菌是一种共同的真菌，通常在包括口腔在内的粘膜表面定殖。在健康的个体中，念珠菌具有非致病性。但是，在免疫缺陷的患者中，例如患有HIV/AIDS的患者，Sjögren综合征，先天性免疫缺陷或接受化学疗法的患者，这种微生物会引起对口腔腔的严重机会感染，称为“鹅口疮”或口咽切念珠菌（OPC）。我们最近发现，对OPC的免疫学高度依赖于IL-23，IL-17和RORγT，从而推翻了长期以来的范式，即TH1细胞和IFNγ介导了对念珠菌的免疫学介导。我们的发现已在影响IL-23/IL-17途径的罕见免疫缺陷疾病的患者中得到了验证，并且患有OPC和其他形式的慢性粘膜皮质念珠菌病（CMC）。例如，Hyper-Ige/Job综合征（HIE）是由STAT3（IL-23下游的转录因子和其他细胞因子）突变引起的。 HIES患者的Th17细胞水平较低，但没有TH1细胞，通常会遭受反复发作的OPC/CMC。同样，具有OPC和CMC的罕见IL-17R缺陷家族。在此提案中，我们将解决有关口腔免疫的几个未解决的问题，强调IL-23/STAT3/IL-17途径。显然，对念珠菌有强大的先天反应，但是这种细胞类型的性质尚不清楚。使用新的记者小鼠，在AIM 1中，我们将确定钥匙IL-17产生的先天细胞类型的性质，该细胞类型为该组织提供了早期响应。在AIM 2中，我们将评估STAT3控制的OPC免疫机制，特别是在口腔上皮细胞中。在AIM 3中，我们将评估IL-23和STAT3信号调节自适应抗Candida Th17响应的机制。总之，这些研究将定义STAT3，IL-23信号传导和IL-17在维持口服粘膜免疫中的作用。