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产生一系列疾病，从尿道炎、宫颈炎到盆腔炎。感染建立的早期事件涉及淋病奈瑟菌与粘膜表面的相互作用，导致炎症介质的局部释放。正因为如此，确定导致炎症的细菌因素和宿主细胞成分是很重要的。先天免疫系统是抵御微生物入侵的第一道防线。toll样受体（TLRs）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。这些种系编码蛋白在专业和非专业免疫细胞中表达程度不同。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，使它们负责提醒邻近的上皮细胞和潜在的免疫细胞感染挑战带来的潜在危险。关于上皮细胞被病原体激活的机制，以及参与这种调节反应的受体和次级介质，我们知之甚少。我们假设性病病原体与粘膜上皮细胞上表达的tlr之间的相互作用负责启动和协调随后的炎症反应。我们之前的研究证实，颈上皮细胞不能表达LPS受体TLR4和相关分子MD-2。相反，它们表达多种其他tlr，这些tlr在功能上似乎能够识别它们的同源配体。其中包括识别细菌脂蛋白的TLR2和识别细菌DNA的TLR9。本研究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先天免疫受体。我们的目标是：(1)表征淋球菌感染过程中TLR2与淋球菌脂蛋白的相互作用；(2)研究细菌DNA和TLR9信号在上皮细胞对奈瑟菌的应答中的作用；(3)检测淋球菌感染过程中激活的信号通路；(4)利用确定的TLR突变体的小鼠生殖道感染模型，研究TLR在淋球菌发病机制中的作用。

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.