Interaction of Chalmydia with Innate Immune Receptors

衣原体与先天免疫受体的相互作用

• 批准号: 7031654
• 负责人: Robin R Ingalls
• 金额: $ 31.44万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031654
• 关键词: Chlamydia trachomatis; bactericidal immunity; cell line; chlamydial disease; clinical research; epithelium; human subject; immunologic receptors; inflammation; pelvic inflammatory disease; phagocytes; receptor binding; reproductive system infection; toll like receptor; Chlamydia trachomatis; bactericidal immunity; cell line; chlamydial disease; clinical research; epithelium; human subject; immunologic receptors; inflammation; pelvic inflammatory disease; phagocytes; receptor binding; reproductive system infection; toll like receptor

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.

描述（由申请人提供）：沙眼衣原体（CT）是美国最常见的细菌性传播感染。 CT的感染通常位于下部生殖道，在那里可以产生尿道或宫颈排放。但是，如果未经治疗，感染可以上升到女性的盐水炎，肝炎和骨盆炎症性疾病（PID）的上层生殖道。据信炎症反应所产生的组织损伤导致输卵管疤痕，输卵管不育症和异位妊娠。尽管它具有临床重要性，但对早期对衣原体的免疫反应知之甚少。从未进行过对CT细胞激活的分子激活分子基础的研究，包括对启动和协调随后的炎症反应的先天免疫受体和次级介质的表征。 我们假设特定的衣原体配体及其先天免疫受体之间的相互作用导致生殖道中局部炎症的发展，因此随后与PID相关的组织损伤。该应用的目标是确定负责在衣原体感染期间创建炎症环境的特定细胞受体和衔接子蛋白，并确定上皮细胞和单核细胞和单核细胞/巨噬细胞在感染期间启动宿主炎症反应的机制。我们将专注于定义Toll样受体（TLR）及其衔接蛋白在衣原体发病机理中的作用，并提出了以下具体目的：（1）表征TLR和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感染期间在上皮细胞和吞噬细胞中激活的信号传导途径； （3）确定CT原发性感染后的细胞变化。 这些研究应产生对衣原体感染的发病机理的新见解，以及较低女性生殖道的先天免疫防御。更好地理解该腔室中免疫反应可能为开发更好的治疗剂和粘膜疫苗的开发铺平了道路，以消除衣原体感染的直接和长期后果。