IL-17 Receptor Signaling in the Oral Mucosa

描述（申请人提供）：口腔是许多感染性病原体的入口。然而，尽管在粘膜免疫领域取得了进展，但令人惊讶的是，人们对口腔黏膜的免疫机制知之甚少。虽然我们对粘膜免疫的了解大多来自胃肠道的研究，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白色念珠菌的研究，这是一种共生的二态真菌，定植于口腔、食管和阴道粘膜表面。在健康个体中，白色念珠菌定植是非致病性的。然而，在艾滋病毒/艾滋病、格林综合征或先天性免疫缺陷等免疫缺陷情况下，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）。OPC在HIV/AIDS中的高发病率（约90%）与CD4+ T细胞对白色念珠菌的免疫有关。直到最近，这被认为是Th1细胞及其标志性细胞因子IFNg的领域。2005年，一种新的T细胞亚群被发现可以产生IL-17，因此被称为“Th17”。产生il -17的细胞在粘膜表面高度富集，特别是胃肠道，并且在艾滋病中被选择性地耗尽。在粘膜念珠菌病的胃肠道模型中，Th1细胞和IFNg似乎具有宿主保护作用，而IL-17和th17诱导的细胞因子IL-23则促进有害的免疫病理。相反，我们小组在小鼠和il - 17r缺乏的人身上的新研究表明，IL-17是抵抗口腔黏膜念珠菌病的重要免疫介质。然而，IL-17驱动宿主防御念珠菌的具体机制尚不清楚，包括口腔黏膜内的靶细胞或IL-17受体介导的下游受体信号机制。本应用程序的目的是填补这一空白，我们的知识，通过特别关注IL-1及其受体在介导口腔白色念珠菌免疫防御中的作用。为此，我们将使用一系列基因靶向小鼠系统地定义OPC背景下重要的IL-17应答细胞类型，并描绘IL-17受体介导宿主防御的特定分子信号通路。

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.