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

描述（由申请人提供）：口腔是许多感染性病原体的入口。尽管在粘膜免疫领域取得了进展，但令人惊讶的是，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，如艾滋病毒/艾滋病患者、Sjögren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）。我们最近发现对OPC的免疫高度依赖于IL-23、IL-17和RORγt，这推翻了长期以来认为对念珠菌的免疫是由Th1细胞和IFNγ介导的范式。我们的研究结果已经在影响IL-23/IL-17途径的罕见免疫缺陷疾病患者中得到验证，这些患者患有OPC和其他形式的慢性粘膜皮肤念珠菌病（CMC）。例如，高ige /Job’s综合征（HIES）是由STAT3突变引起的，STAT3是IL-23和其他细胞因子的下游转录因子。HIES患者Th17细胞水平较低，但Th1细胞水平不高，通常复发性OPC/CMC。同样，罕见的il - 17r缺陷家族存在于OPC和CMC。在本提案中，我们将解决关于念珠菌口服免疫的几个悬而未决的问题，强调IL-23/STAT3/IL- 17途径。很明显，对念珠菌有强大的先天反应，但这种细胞类型的性质尚不清楚。使用新的报告小鼠，在Aim 1中，我们将确定关键的产生il -17的先天细胞类型的性质，这种细胞类型提供了对这种生物体的早期反应。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信号调节适应性抗假丝酵母Th17反应的机制。这些研究将共同确定STAT3、IL-23信号和IL-17在维持口腔黏膜免疫中的作用。

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.