Interaction of Chalmydia with Innate Immune Receptors

描述(申请人提供)：沙眼衣原体(CT)是美国最常见的细菌性性传播感染。沙眼衣原体感染通常局限于下生殖道，在那里它会产生尿路或宫颈分泌物。然而，如果不进行治疗，感染可能会上升到上生殖道，在女性中产生输卵管炎、周围肝炎和盆腔炎(PID)。炎症反应造成的组织损伤被认为会导致输卵管疤痕、输卵管不孕和异位妊娠。尽管衣原体具有重要的临床意义，但人们对衣原体的早期免疫反应知之甚少。CT激活细胞的分子基础，包括启动和协调随后炎症反应的先天免疫受体和次级介质的特征，从未进行过研究。 我们推测，特定的衣原体配体和它们的天然免疫受体之间的相互作用导致生殖道局部炎症的发展，从而导致与产后出血相关的组织损伤。这项应用的目标是确定在衣原体感染过程中负责创造炎症环境的特定细胞受体和适配器蛋白，并确定在上皮细胞和单核/巨噬细胞感染期间宿主炎症反应的启动机制。我们将重点研究Toll样受体(Toll-like Receptor，TLRs)及其接头蛋白在衣原体致病中的作用，并提出以下具体目标：(1)研究TLRs与CT在上皮细胞和吞噬细胞生产性感染过程中的相互作用；(2)确定CT感染过程中上皮细胞和吞噬细胞中激活的信号通路；(3)确定CT初次感染后的细胞变化。 这些研究应该会对衣原体感染的发病机制以及女性生殖道下部的先天免疫防御产生新的见解。更好地了解这一间隔内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.