Host Defense in Oral Candidiasis

描述(由申请人提供)：宿主防御系统的紊乱可导致病原体过度生长，如白色念珠菌，导致疼痛和虚弱的状况，口咽部念珠菌病(OPC)。由于衰老、化疗或免疫缺陷，免疫反应不足会增加OPC的风险。由于艾滋病的流行，这些疾病正在重新出现，无论是在没有HAART的不发达世界，还是在出现抗药性的情况下。致炎细胞因子IL-1在宿主抵抗播散性和粘膜念珠菌感染中起关键作用，但其产生IL-1或IL-1介导的保护OPC的机制尚不清楚。我们已经开发了一种OPC小鼠模型，将用于确定体内调节IL-1(3)产生的先天免疫机制，并将在体外开发系统来详细定义这些机制。急性炎症反应是通过胚系编码的模式识别受体(PRRs)产生的，这种受体识别病原体上的特定分子结构，称为病原体相关分子模式(PAMPs)。Toll样受体是一类膜结合的PRRs，表达于宿主细胞，包括人口腔上皮细胞(HOECs)。除了TLRs，一个被称为Nacht-LRRs(NLRs)或炎症体的细胞质PRRs大家族也与先天性反应有关，特别是在未成熟形式的IL-1(PRO-IL-1)的处理中。需要检验的中心假设是，真菌病原体与口腔粘膜上的TLRs(有或没有TLR2共受体，Dectin-1)或NLRs的相互作用对于控制口腔中的念珠菌感染至关重要，而诱导IL-1P对保护至关重要。我们提出的具体目标如下：1)确定在OPC局部和播散性感染的发病机制中关键的PRRs，2)确定NLR家族在念珠菌感染中诱导、加工和释放IL-1P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对口腔白色念珠菌的防御的天然免疫受体和途径，并开发宿主免疫调节和抗真菌治疗的新方法。

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.