Host Defense in Oral Candidiasis

口腔念珠菌病的宿主防御

• 批准号: 7848268
• 负责人: Amy G Hise
• 金额: $ 34.46万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-22 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848268
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Acute; Adult; Age; Antifungal Agents; Binding; Candida; Candida albicans; Caspase-1; Cells; Complex; Disease; Down-Regulation; Drug resistance; Epithelial; Epithelial Cells; Equilibrium; Family; Genetic Transcription; Germ Lines; Goals; Growth; Highly Active Antiretroviral Therapy; Host Defense; Human; Immune; Immune response; Immunologic Receptors; In Vitro; Infant; Infection; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Ligands; Mediating; Membrane; Microbe; Modality; Modeling; Molecular; Molecular Structure; Mus; Neonatal; Oral; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Pain; Pathogenesis; Pathway interactions; Pattern; Pattern recognition receptor; Predisposition; Prevalence; Process; Production; Research Personnel; Risk; Role; Signal Transduction Pathway; Signaling Molecule; System; TLR1 gene; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Transcriptional Regulation; age related; chemotherapy; cytokine; dectin 1; immunoregulation; in vivo; mouse model; neonate; novel strategies; oral bacteria; oral cavity epithelium; oral pathogen; oropharyngeal thrush; pathogen; procaspase-1; programs; receptor; receptor expression; research study; response

DESCRIPTION (provided by applicant): Perturbations in host defenses can result in overgrowth of pathogens such as Candida albicans, resulting in a painful and debilitating condition, oropharyngeal candidiasis (OPC). Inadequate immune responses, through aging, chemotherapy or immune deficiency, are associated with increased risk of OPC. These disorders are reemerging due to the prevalence of AIDS, both in the underdeveloped world where HAART is not available, and in cases where drug resistance develops. The proinflammatory cytokine, interleukin-1 is critical in host defense against both disseminated and mucosal Candida infections yet the mechanisms that underlie the production of IL-1 or of IL-1-mediated protection in OPC are unknown. We have developed a mouse model of OPC that will be utilized to determine the innate immune mechanisms regulating IL-1 (3 production in vivo and will develop in vitro systems to define these mechanisms in molecular detail. Acute inflammatory responses are generated via germ-line encoded pattern-recognition receptors (PRRs) that recognize specific molecular structures on pathogens known as pathogen associated molecular patterns (PAMPs). Toll-like receptors (TLRs) constitute a class of membrane bound PRRs expressed on host cells, including human oral epithelial cells (HOECs). In addition to TLRs, a large family of cytoplasmic PRRs known as the NACHT-LRRs (NLRs) or inflammasome have been implicated in innate responses, particularly in the processing of the immature form of IL-1 (pro-IL-1). The central hypothesis to be tested is that interactions of fungal pathogens with TLRs (with or without the TLR2 co-receptor, dectin-1) or NLRs at the oral mucosa are critical for controlling Candida infections in the oral cavity and that induction of IL-1P is critical for protection. We propose the following specific aims: 1) To identify critical PRRs involved in the pathogenesis of localized and disseminated infection in OPC, 2) To define the potential role of the NLR family in the induction, processing and release of IL-1P in Candida infections. The ontogeny of expression and function of these innate PRRs will be defined. The long term goals of this project are to determine the innate immune receptors and pathways involved in host defense against the oral pathogen Candida albicans and develop novel approaches to host immunomodulation and anti-fungal therapeutic modalities.

描述（由申请人提供）：宿主防御的扰动可能导致白色念珠菌等病原体过度生长，从而导致口咽念珠菌病 (OPC) 的痛苦和衰弱状况。由于衰老、化疗或免疫缺陷导致的免疫反应不足，与 OPC 风险增加相关。由于艾滋病的流行，这些疾病正在重新出现，无论是在无法进行高效抗逆转录病毒治疗的欠发达国家，还是在出现耐药性的情况下。促炎细胞因子 IL-1 对于宿主防御播散性和粘膜念珠菌感染至关重要，但 OPC 中产生 IL-1 或 IL-1 介导的保护作用的机制尚不清楚。我们开发了一种 OPC 小鼠模型，将用于确定调节体内 IL-1（3）产生的先天免疫机制，并将开发体外系统以在分子细节上定义这些机制。急性炎症反应是通过种系产生的编码的模式识别受体（PRR）识别病原体上的特定分子结构，称为病原体相关分子模式（PAMP）（TLR），构成一类在宿主细胞（包括人类口腔细胞）上表达的膜结合PRR。除了 TLR 之外，称为 NACHT-LRR (NLR) 或炎症小体的一大类细胞质 PRR 也与先天反应有关，特别是在未成熟形式的 IL-1（pro-1）的加工中。要测试的中心假设是真菌病原体与 TLR 的相互作用（有或没有 TLR2 辅助受体 dectin-1）或口腔粘膜的 NLR 对于控制口腔念珠菌感染至关重要，而 IL-1P 的诱导对于保护至关重要。我们提出以下具体目标：1) 确定 OPC 局部和播散性感染发病机制中涉及的关键 PRR，2) 确定 NLR 家族在念珠菌感染中诱导、加工和释放 IL-1P 中的潜在作用。这些先天 PRR 的表达和功能的个体发育将被定义。该项目的长期目标是确定参与宿主防御口腔病原体白色念珠菌的先天免疫受体和途径，并开发宿主免疫调节和抗真菌治疗方式的新方法。