IL-17 Receptor Signaling in the Oral Mucosa

描述（由申请人提供）：口腔是许多感染性病原体的入口。然而，尽管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知之甚少。虽然我们对粘膜免疫的理解大多来自于胃肠道的研究，但其他粘膜部位的免疫并不总是与肠道平行。这种二分法的一个很好的例子来自于对白色念珠菌的研究，白色念珠菌是一种寄生在口腔、食管和阴道粘膜表面的二型真菌。在健康个体中，C.白色念珠菌定殖是非致病性的。然而，在免疫缺陷的情况下，如艾滋病毒/艾滋病，干燥综合征或先天性免疫缺陷，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）。在HIV/AIDS中OPC的高发生率（>90%）暗示了CD 4 + T细胞在抗C.白色念珠菌。直到最近，这被认为是Th 1细胞及其标志性细胞因子IFNg的领域。在2005年，发现了一种新的T细胞亚群，其产生IL-17，因此被称为“Th 17”。“IL-17产生细胞在粘膜表面，特别是胃肠道高度富集，并在艾滋病中选择性耗尽。在粘膜念珠菌病的胃肠道模型中，Th 1细胞和IFNg似乎是宿主保护性的，而IL-17和Th 17诱导性细胞因子IL-23促进有害的免疫病理学。相比之下，我们小组在小鼠中的工作和在IL-17 R缺乏的人中的新研究表明，IL-17是抵抗口腔粘膜念珠菌病的免疫力的重要介质。然而，IL-17驱动宿主防御念珠菌的具体机制尚不清楚，包括口腔粘膜内的靶细胞或由IL-17受体介导的下游受体信号传导机制。本申请的目的是填补我们知识中的这一空白，通过特别关注IL-1及其受体在介导口腔中对白色念珠菌的免疫防御中的作用。为此，我们将使用一系列基因靶向小鼠来系统地定义OPC背景下重要的IL-17响应细胞类型，并描绘IL-17受体用于介导宿主防御的特定分子信号通路。 公共卫生相关性：口腔念珠菌病，也称为口腔鹅口疮，是一种口腔粘膜的艾滋病定义真菌感染。这种疾病也困扰着接受化疗的个体、服用免疫抑制药物的移植患者、使用吸入性皮质类固醇药物的哮喘患者或免疫功能受损的其他人，如婴儿和老年人。该项目的目的是详细了解免疫系统如何控制口腔念珠菌病，重点是特定细胞因子受体IL-17 R的作用。这项研究的长期目标是为口腔粘膜疾病开发更好的疗法或疫苗，并了解抑制特定免疫事件的疗法的后果。

DESCRIPTION (provided by applicant): The oral cavity is a portal of entry for many infectious pathogens. However, despite advances in the field of mucosal immunity, mechanisms of immunity in the oral mucosa are surprisingly poorly understood. Whereas much of our understanding of mucosal immunity comes from studies of the gastrointestinal tract, immunity at other mucosal sites does not always parallel the gut. A good example of this dichotomy comes from studies of Candida albicans, a commensal dimorphic fungus that colonizes oral, esophageal and vaginal mucosal surfaces. In healthy individuals, C. albicans colonization is non-pathogenic. However, in conditions of immunodeficiency such as HIV/AIDS, Sj¿gren's syndrome or congenital immunodeficiency, this microbe causes severe opportunistic infections of the oral cavity, known as "thrush" or oropharyngeal candidiasis (OPC). The high incidence of OPC in HIV/AIDS (>90%) implicates CD4+ T cells in immunity against C. albicans. Until recently, this was thought to be the province of Th1 cells and their signature cytokine, IFNg. In 2005, a new subset of T cell was discovered that produces IL-17, and hence is known as "Th17." IL-17-producing cells are highly enriched at mucosal surfaces, particularly the GI tract, and are selectively depleted in AIDS. In a gastrointestinal model of mucosal candidiasis, Th1 cells and IFNg appear to be host-protective, whereas IL-17 and the Th17-inductive cytokine IL-23 promote a deleterious immunopathology. In contrast, work from our group in mice and new studies in IL-17R-deficient humans indicate that IL-17 is an essential mediator of immunity against oral mucosal candidiasis. However, the specific mechanisms by which IL-17 drives host defense against Candida is not known, including the target cells within the oral mucosa or the downstream receptor signaling mechanisms mediated by the IL-17 receptor. The objective of this application is to fill this gap in our knowledge, by focusing specifically on the role of IL-1 and its receptor in mediating immune defense against Candida albicans in the oral cavity. To that end, we will use a series of gene-targeted mice to systematically define the important IL-17-responsive cell types in the context of OPC, and to delineate specific molecular signaling pathways used by the IL-17 receptor to mediate host defense. PUBLIC HEALTH RELEVANCE: Oral candidiasis, also known as oral thrush, is an AIDS-defining fungal infection of the oral mucosa. This disease also afflicts individuals on chemotherapy, transplant patients taking immunosuppressive drugs, asthma patients using inhaled corticosteroid drugs or others with compromised immune function such as infants and the elderly. The objective of this project is to understand in detail how the immune system normally keeps oral candidiasis under control, with an emphasis on the role of a particular cytokine receptor, the IL-17R. The long-term goal of this research is to develop better therapies or vaccines for mucosal disease of the oral cavity, and to understand the consequences of therapies that suppress specific immune events.