Interaction of Chalmydia with Innate Immune Receptors

描述（由申请方提供）：沙眼衣原体（CT）是美国最常见的细菌性性传播感染。CT感染通常局限于下生殖道，在那里它可以产生尿道或宫颈分泌物。然而，如果不及时治疗，感染可以上升到上生殖道，在妇女中产生输卵管炎、肝炎周围和盆腔炎（PID）。由炎症反应引起的组织损伤被认为是导致输卵管瘢痕形成、输卵管不孕和异位妊娠的原因。尽管其临床重要性，很少有人知道衣原体的早期免疫反应。CT细胞激活的分子基础的调查，包括先天免疫受体和继发介质的启动和协调随后的炎症反应的表征，从来没有进行过。 我们假设特异性衣原体配体与其先天免疫受体之间的相互作用导致生殖道局部炎症的发展，因此导致随后与PID相关的组织损伤。本申请的目的是鉴定在衣原体感染期间负责产生炎症环境的特定细胞受体和衔接蛋白，并确定在上皮细胞和单核细胞/巨噬细胞感染期间启动宿主炎症反应的机制。本论文的主要目的是：（1）研究衣原体感染上皮细胞和吞噬细胞过程中Toll样受体（TLRs）与衣原体之间的相互作用，（2）研究衣原体感染上皮细胞和吞噬细胞过程中TLRs与衣原体之间的信号通路，（3）研究衣原体感染上皮细胞和吞噬细胞过程中TLRs与衣原体之间的相互作用。（3）观察CT初次感染后细胞的变化。 这些研究将为衣原体感染的发病机制以及女性下生殖道的先天免疫防御机制提供新的见解。更好地了解这一区室的免疫反应可以为开发更好的治疗剂和粘膜疫苗铺平道路，以对抗衣原体感染的直接和长期后果。

DESCRIPTION (provided by the applicant): Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection in the United States. Infection with CT usually remains localized to the lower genital tract where it can produce urethral or cervical discharge. However, if left untreated, the infection can ascend to the upper genital tract producing salpingitis, perihepatitis and pelvic inflammatory disease (PID) in women. The resultant tissue damage from the inflammatory response is believed to result in fallopian tube scarring, tubal infertility and ectopic pregnancy. In spite of its clinical importance, little is known about the early immune responses to chlamydia. An investigation into the molecular basis of cellular activation by CT, including a characterization of the innate immune receptors and secondary mediators that initiate and coordinate the subsequent inflammatory response, has never been undertaken. We hypothesize that the interactions between specific chlamydial ligands and their innate immune receptors leads to the development of localized inflammation in the genital tract, and therefore the subsequent tissue damage associated with PID. The goals of this application are to identify the specific cellular receptors and adaptor proteins that are responsible for creating an inflammatory environment during chlamydial infection, and to determine the mechanism by which the host inflammatory response is initiated during infection of both epithelial cells and monocytes/macrophages. We will focus on defining the role of the Toll-like receptors (TLRs) and their adaptor proteins in chlamydial pathogenesis, and have proposed the following specific aims: (1) To characterize the interactions between TLRs and CT during a productive infection of epithelial cells and phagocytic cells; (2) To identify the signaling pathways activated in epithelial cells and phagocytic cells during CT infection; (3) To determine the cellular changes that follow primary infection with CT. These studies should yield novel insights into the pathogenesis of chlamydial infections, as well as the innate immune defenses of the lower female genital tract. A better understanding of the immune response in this compartment could pave the way for the development of better therapeutic agents and mucosal vaccines to combat the immediate and long-term consequences of chlamydial infections.