Innate Immune Receptors in Host Responses to Neisseria

描述(申请人提供)：人类病原体淋病奈瑟氏菌产生一系列疾病，从尿道炎和宫颈炎症到盆腔炎。感染形成的早期事件涉及淋球菌与粘膜表面的相互作用，导致局部炎性介质的释放。正因为如此，确定导致炎症的细菌因素和宿主细胞成分是重要的。先天免疫系统是抵御入侵微生物的第一道防线。Toll样受体是这种先天免疫防御的一部分，识别保守的微生物模式，并启动引导炎症反应的信号转导途径。这些生殖系编码蛋白在专业和非专业免疫细胞中都有不同程度的表达。排列在粘膜表面的上皮细胞通常是微生物接触的初始位置，使它们负责提醒邻近的上皮细胞和潜在的免疫细胞感染挑战构成的潜在危险。关于病原体激活上皮细胞的机制，以及参与这一调节反应的受体和次级介质，目前还知之甚少。我们推测，STD病原体与黏膜上皮细胞上表达的TLRs之间的相互作用负责启动和协调随后的炎症反应。我们以前的工作证实，宫颈上皮细胞不表达内毒素受体TLR4及其相关分子MD-2。相反，它们表达各种其他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TLR2和用于识别细菌DNA的TLR9。这一建议的目的是确定泌尿生殖道中负责识别淋病奈瑟菌和启动免疫反应的天然免疫受体。我们的目标是：(1)表征淋球菌感染过程中TLR2和淋球菌脂蛋白之间的相互作用；(2)检测细菌DNA和TLR9信号在奈瑟氏菌上皮细胞反应中的作用；(3)检测淋球菌感染过程中激活的信号通路；(4)利用已定义的TLR突变体的生殖道感染小鼠模型，研究TLRs在淋病发病中所起的作用。

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.