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

• 批准号: 8611195
• 负责人: Sarah L Gaffen
• 金额: $ 38.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8611195
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Adrenal Cortex Hormones; Adverse effects; Antibodies; Antifungal Agents; Antigen Receptors; Asthma; 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; Interferons; Interleukin-17; Job' 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' s Syndrome; Surface; T-Lymphocyte; Th1 Cells; Tissues; Transplant Recipients; Vaccines; adaptive immunity; antimicrobial; 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

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 ROR?t, overturning the long-held paradigm that immunity to Candida is mediated by Th1 cells and IFN?. 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（由申请人提供）：口腔是许多传染性病原体的进入门户。尽管粘膜免疫领域取得了进展，但令人惊讶的是，人们对口腔粘膜的免疫机制仍然知之甚少。白色念珠菌是一种共生真菌，通常定植于包括口腔在内的粘膜表面。在健康个体中，念珠菌是非致病性的。然而，在免疫缺陷患者中，例如艾滋病毒/艾滋病患者、干燥综合征患者、先天性免疫缺陷患者或接受化疗的患者，这种微生物会导致严重的口腔机会性感染，称为“鹅口疮”或口咽念珠菌病 (OPC)。我们最近发现OPC免疫高度依赖于IL-23、IL-17和ROR?t，颠覆了长期以来认为念珠菌免疫由Th1细胞和IFN?介导的模式。我们的研究结果已在患有影响 IL-23/IL-17 通路的罕见免疫缺陷疾病以及患有 OPC 和其他形式的慢性皮肤粘膜念珠菌病 (CMC) 的患者中得到验证。例如，高 IgE/乔布氏综合症 (HIES) 是由 STAT3 突变引起的，STAT3 是 IL-23 和其他细胞因子下游的转录因子。 HIES 患者的 Th17 细胞水平较低，但 Th1 细胞水平较低，并且通常患有复发性 OPC/CMC。同样，罕见的 IL-17R 缺陷家族也存在 OPC 和 CMC。在本提案中，我们将解决有关念珠菌口服免疫的几个未解答的问题，重点是 IL-23/STAT3/IL-17 途径。很明显，念珠菌有一种强大的先天反应，但这种细胞类型的性质尚不清楚。使用新的报告小鼠，在目标 1 中，我们将确定关键的产生 IL-17 的先天细胞类型的性质，该细胞类型为该生物体提供早期反应。在目标 2 中，我们将评估 STAT3 控制的 OPC 免疫机制，特别是口腔上皮细胞中的免疫机制。在目标 3 中，我们将评估 IL-23 和 STAT3 信号传导调节适应性抗念珠菌 Th17 反应的机制。这些研究将共同​​确定 STAT3、IL-23 信号传导和 IL-17 在维持口腔粘膜免疫中的作用。