Innate Immune Receptors in Host Responses to Neisseria

描述（由申请人提供）：人类病原体淋病奈瑟菌可引起一系列疾病，包括尿道炎、宫颈炎和盆腔炎。感染建立的早期事件涉及N.淋病和粘膜表面，导致局部释放炎症介质。因此，重要的是要确定有助于炎症的细菌因子和宿主细胞成分。先天免疫系统是抵御微生物入侵的第一道防线。Toll样受体（TLR）是这种先天免疫防御的一部分，识别保守的微生物模式并启动指导炎症反应的信号转导途径。这些生殖系编码的蛋白质在专业和非专业免疫细胞中以不同程度表达。排列在粘膜表面的上皮细胞通常是微生物接触的初始部位，使它们负责警告相邻上皮和下面的免疫细胞由感染性挑战构成的潜在危险。关于病原体激活上皮细胞的机制以及参与这种调节反应的受体和次级介质知之甚少。我们推测，性病病原体和粘膜上皮细胞上表达的TLR之间的相互作用是负责启动和协调随后的炎症反应。我们先前的工作证实宫颈上皮细胞不能表达LPS受体TLR 4和相关分子MD-2。相反，它们表达各种其他TLR，这些TLR似乎在功能上能够识别它们的同源配体。这包括用于识别细菌脂蛋白的TLR 2和用于识别细菌DNA的TLR 9。这项建议的目的是确定先天性免疫受体在泌尿生殖道是负责识别N。淋病和免疫反应的启动。我们的目标是：（1）表征淋球菌感染期间TLR 2和淋球菌脂蛋白之间的相互作用;（2）检查细菌DNA和TLR 9信号传导在上皮细胞对奈瑟氏球菌的应答中的作用;（3）检查淋球菌感染期间激活的信号传导途径;以及（4）使用确定的TLR突变体中的生殖道感染的小鼠模型检查TLR在淋球菌发病机制中发挥的作用。

DESCRIPTION (provided by applicant): The human pathogen Neisseria gonorrhoeae produces an array of diseases ranging from urethritis and cervicitis to pelvic inflammatory disease. Early events in the establishment of infection involve interactions between N. gonorrhoeae and the mucosal surface, which lead to the local release of inflammatory mediators. Because of this, it is important to identify the bacterial factors and host cell components that contribute to inflammation. The innate immune system is the first line of defense against invading microorganisms. Toll-like receptors (TLRs) are a part of this innate immune defense, recognizing conserved microbial patterns and initiating signal transduction pathways that direct the inflammatory response. These germ-line encoded proteins are expressed to varying degrees in both professional and non-professional immune cells. Epithelial cells that line the mucosal surface are often the initial site of contact for microorganisms, making them responsible for alerting adjacent epithelium and the underlying immune cells of the potential danger posed by an infectious challenge. Little is known about the mechanism of epithelial cell activation by pathogens, and the receptors and secondary mediators involved in this regulated response. We hypothesize that the interactions between STD pathogens and the TLRs expressed on mucosal epithelial cells are responsible for initiating and coordinating the subsequent inflammatory response. Our previous work established that cervical epithelial cells fail to express the LPS receptor TLR4 and the associated molecule MD-2. In contrast, they express a variety of other TLRs that appear to be functionally capable of recognizing their cognate ligands. This includes TLR2 for the recognition of bacterial lipoproteins and TLR9 for the recognition of bacterial DNA. The goal of this proposal is to identify the innate immune receptors in the urogenital tract that are responsible for the recognition of N. gonorrhoeae and the initiation of the immune response. We aim to: (1) characterize the interactions between TLR2 and gonococcal lipoproteins during gonococcal infections; (2) examine the role of bacterial DNA and TLR9 signaling in epithelial cell responses to Neisseria; (3) examine the signaling pathways activated during gonococcal infection; and (4) examine the role played by TLRs in gonococcal pathogenesis using the mouse model for genital tract infection in defined TLR mutants.