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，对口腔粘膜中的免疫机制仍然知之甚少。白色念珠菌是一种常见于口腔粘膜表面的真菌。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，如患有艾滋病毒/艾滋病、舍格伦综合征、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”或口咽念珠菌病（OPC）。我们最近发现，免疫OPC是高度依赖于IL-23，IL-17，和ROR？t，推翻了长期以来认为对念珠菌的免疫是由Th 1细胞和IFN？介导的范式。我们的研究结果已在影响IL-23/IL-17通路的罕见免疫缺陷疾病患者以及患有OPC和其他形式的慢性粘膜皮肤念珠菌病（CMC）的患者中得到验证。例如，高IgE/约伯综合征（HIES）由STAT 3（IL-23和其他细胞因子下游的转录因子）的突变引起。HIES患者具有低水平的Th 17细胞，但不是Th 1细胞，并且通常患有复发性OPC/CMC。类似地，罕见的IL-17 R缺陷家族存在OPC和CMC。在这个提案中，我们将解决几个悬而未决的问题，关于口服免疫念珠菌，强调IL-23/STAT 3/IL- 17通路。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，在目标1中，我们将确定关键的IL-17产生先天细胞类型的性质，该细胞类型提供对该生物体的早期反应。在目标2中，我们将评估由STAT 3控制的对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STAT 3信号转导调节适应性抗念珠菌Th 17应答的机制。总之，这些研究将确定STAT 3，IL-23信号转导和IL-17在维持口腔粘膜免疫中的作用。

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 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.