Host Defense in Oral Candidiasis

宿主防御的扰动可导致病原体如白色念珠菌的过度生长， 口咽念珠菌病（OPC）是一种令人痛苦和虚弱的疾病。免疫反应不足， 通过衰老，化疗或免疫缺陷，与OPC的风险增加有关。这些 由于艾滋病的流行，疾病正在重新出现，无论是在HAART的不发达国家， 没有，并在耐药性发展的情况下。促炎细胞因子白细胞介素-1是 在宿主防御播散性和粘膜念珠菌感染中至关重要， OPC中IL-1产生或IL-1介导的保护作用的机制尚不清楚。我们已经开发出一种 OPC小鼠模型，将用于确定调节IL-1的先天免疫机制（3 在体内生产，并将开发体外系统，以确定这些机制的分子细节。急性 炎症反应是通过生殖系编码的模式识别受体（PRR）产生的， 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）。Toll样受体（TLR）构成一类在宿主细胞上表达的膜结合PRR， 包括人口腔上皮细胞（HOEC）。除了TLR，细胞质PRRs的一个大家族 称为NACHT-LRR（NLR）或炎性小体的蛋白质与先天性反应有关，特别是 在IL-1的未成熟形式（pro-IL-1）的加工中。有待检验的中心假设是， 真菌病原体与TLR（有或没有TLR 2共受体，dectin-1）或NLR的相互作用， 口腔粘膜对控制口腔念珠菌感染至关重要， 至关重要的保护。我们提出了以下具体目标：1）确定涉及的关键PRR 2）确定NLR在OPC中的潜在作用 在念珠菌感染中IL-1 P的诱导、加工和释放中，表达的个体发生 这些先天PRR的功能将被定义。该项目的长期目标是确定 天然免疫受体和参与宿主防御口腔病原体白色念珠菌的途径 并开发宿主免疫调节和抗真菌治疗方式的新方法。

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.