Host Defense in Oral Candidiasis

口腔念珠菌病的宿主防御

• 批准号: 7840840
• 负责人: Amy G Hise
• 金额: $ 1.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-16 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840840
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Acute; Adult; Age; Aging; 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

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-1or 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 systemsto 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.

宿主防御的扰动可能导致病原体（例如白色念珠菌）的过度生长，导致 痛苦而令人衰弱的状况，口咽念珠菌病（OPC）。免疫反应不足， 通过衰老，化学疗法或免疫缺陷与OPC风险增加有关。这些 由于艾滋病的流行，疾病正在重新出现 不可用，并且在耐药性发展的情况下。促炎细胞因子，白介素1是 对宿主防御的抗衡性至关重要 IL-1介导的OPC保护IL-1OR的产生是未知的。我们已经开发了 OPC的小鼠模型将用于确定调节IL-1的先天免疫机制（3 体内生产，并将在体外系统发展，以分子细节定义这些机制。急性 炎症反应是通过种系编码的模式识别受体（PRR）产生的，该受体（PRR） 在称为病原体相关的分子模式的病原体上识别特定的分子结构 （小型小型）。 Toll样受体（TLR）构成了在宿主细胞上表达的一类膜结合的PRR， 包括人口腔上皮细胞（HOEC）。除了TLR，大型细胞质PRR家族 被称为NACHT-LRRS（NLR）或炎症组已与先天反应有关，特别是 在处理IL-1的未成熟形式（Pro-IL-1）中。要测试的中心假设是 真菌病原体与TLR（有或没有TLR2共受体，Dectin-1）或NLR的相互作用 口服粘膜对于控制口腔中的念珠菌感染至关重要，而IL-1P的诱导是 保护至关重要。我们提出以下具体目的：1）确定涉及的关键PRR OPC中局部和传播感染的发病机理，2）定义NLR的潜在作用 在念珠菌感染中IL-1P的诱导，加工和释放中的家族。表达的个体发育 这些先天PRR的功能将被定义。该项目的长期目标是确定 与口腔病原体白色念珠菌有关的先天免疫受体和途径涉及宿主防御 并开发新的方法来托管免疫调节和抗真菌治疗方式。