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: 9193080
• 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
• 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/9193080
• 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; Hematopoietic; Human; IgE; Image; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Impairment; In Situ; Individual; Infant; Infection; Interferon Type II; Interleukin-17; Job' s Syndrome; Kinetics; Light; Maintenance; Mediating; Microbe; Mouse Strains; Mouth Diseases; Mucocutaneous Candidiasis; 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 Transduction; Sjogren' s Syndrome; Stat3 Signaling Pathway; Surface; Symbiosis; 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; public health relevance; 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 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(申请人提供)：口腔是许多传染性病原体的入口。尽管在黏膜免疫领域取得了进展，但令人惊讶的是，口腔粘膜中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。在健康的个体中，念珠菌是非致病的。然而，在免疫缺陷患者中，如艾滋病毒/艾滋病、干燥综合征、先天性免疫缺陷或接受化疗的患者，这种微生物会导致严重的口腔机会性感染，称为“鹅口疮”或口咽部念珠菌病(OPC)。我们最近发现，对OPC的免疫高度依赖于IL-23、IL-17和rORγt，颠覆了长期以来认为对念珠菌的免疫是由Th1细胞和干扰素γ介导的范式。我们的发现在患有影响IL-23/IL-17途径的罕见免疫缺陷疾病以及患有OPC和其他形式的慢性黏膜皮肤念珠菌病(CMC)的患者中得到了验证。例如，高IgE/乔布斯综合征(HIEs)是由STAT3突变引起的，STAT3是IL-23下游的一种转录因子和其他细胞因子。HIES患者Th17细胞水平较低，但Th1细胞水平较低，且常复发OPC/CMC。同样，罕见的IL-17R缺陷家系存在OPC和CMC。在这项提案中，我们将解决几个关于口服免疫念珠菌的未回答问题，重点是IL-23/STAT3/IL-17途径。很明显，对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。利用新的报告小鼠，在目标1中，我们将确定产生IL-17的关键先天细胞类型的性质，这种细胞类型提供对这种有机体的早期反应。在目标2中，我们将评估STAT3调控的OPC的免疫机制，特别是在口腔上皮细胞中。在目标3中，我们将评估IL-23和STAT3信号调节适应性抗念珠菌Th17应答的机制。总之，这些研究将确定STAT3、IL-23信号和IL-17在维持口腔粘膜免疫中的作用。