IL-17 Receptor Signaling in the Oral Mucosa

口腔粘膜中的 IL-17 受体信号传导

• 批准号: 8270744
• 负责人: Sarah L Gaffen
• 金额: $ 36.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270744
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adoptive Transfer; Adrenal Cortex Hormones; Asthma; Bone Marrow; Breathing; CD4 Positive T Lymphocytes; Candida; Candida albicans; Candidiasis; Cells; Cytokine Receptors; Cytoplasmic Tail; Data; Disease; Distal; Elderly; Epithelial Cells; Esophageal; Event; Exhibits; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Goals; Hematopoietic; Host Defense; Human; Immune; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunosuppressive Agents; In Vitro; Incidence; Individual; Industrial fungicide; Infant; Infection; Interleukin-1; Interleukin-17; Keratin; Knock-in Mouse; Knowledge; Location; MAP Kinase Gene; Mediating; Mediator of activation protein; Microbe; Modeling; Molecular; Mouth Diseases; Mucosal Immunity; Mus; Mutation; Mycoses; NF-kappa B; Neutrophil Infiltration; Opportunistic Infections; Oral; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Point Mutation; Predisposition; Proteins; Province; Receptor Signaling; Research; Resistance; Role; Saliva; Salivary Glands; Series; Signal Pathway; Signal Transduction; Surface; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Tissues; Transgenic Mice; Translations; Transplant Recipients; Vagina; Work; Yeasts; antimicrobial; aquaporin 5; cell type; chemotherapy; congenital immunodeficiency; cytokine; defined contribution; fungus; gastrointestinal; immune function; immunopathology; in vivo; interleukin-23; mucosal site; mucosal vaccine; oral cavity epithelium; oral fungal; oral infection; oropharyngeal thrush; pathogen; protective effect; receptor; response

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.

描述（由申请人提供）：口腔是许多传染性病原体的进入门户，然而，尽管粘膜免疫领域取得了进展，但令人惊讶的是，我们对粘膜的了解却很少。免疫来自胃肠道的研究，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对共生白色念珠菌的研究。在健康个体中，白色念珠菌的定植是非致病性的，但在艾滋病毒/艾滋病等免疫缺陷的情况下。格伦氏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)。 HIV/AIDS 中 OPC 的高发病率 (>90%) 表明 CD4+ T 细胞具有抵抗免疫力。直到最近，这还被认为是 Th1 细胞及其标志性细胞因子 IFNg 的领域。2005 年，这是一个新的亚群。发现 T 细胞产生 IL-17，因此被称为“Th17”。产生 IL-17 的细胞在粘膜表面（特别是胃肠道）高度富集，并且在 AIDS 胃肠道模型中选择性地减少。在粘膜念珠菌病中，Th1 细胞和 IFNg 似乎具有宿主保护作用，而 IL-17 和 Th17 诱导细胞因子 IL-23 会促进有害的免疫病理学。相比之下，我们小组对 IL-17R 缺陷小鼠和新人类的研究表明，IL-17 是针对口腔粘膜念珠菌病的免疫的重要介质。然而，IL-17 驱动宿主防御念珠菌的具体机制。未知，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。本申请的目的是通过专门关注 IL-1 的作用来填补我们的知识空白。及其受体介导口腔中针对白色念珠菌的免疫防御。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 反应细胞类型。 IL-17 受体用于介导宿主防御的特定分子信号传导途径。 公共卫生相关性：口腔念珠菌病，也称为口腔鹅口疮，是一种口腔粘膜真菌感染，这种疾病也影响接受化疗的患者、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其他免疫功能低下的患者。该项目的目的是详细了解免疫系统通常如何控制口腔念珠菌病。这项研究的长期目标是开发针对口腔粘膜疾病的更好的疗法或疫苗，并了解抑制特定免疫事件的疗法的后果。