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

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 感染通常局限于下生殖道，可产生尿道或宫颈分泌物。然而，如果不及时治疗，感染可能会上升到上生殖道，导致女性出现输卵管炎、肝周炎和盆腔炎 (PID)。据信，炎症反应造成的组织损伤会导致输卵管疤痕、输卵管不孕和宫外孕。尽管其临床重要性，但人们对衣原体的早期免疫反应知之甚少。从未通过 CT 对细胞激活的分子基础进行过研究，包括对先天免疫受体和启动和协调后续炎症反应的次级介质的表征。 我们假设特定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，从而导致与 PID 相关的后续组织损伤。该应用的目标是识别在衣原体感染期间负责创建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。我们将重点定义Toll样受体（TLR）及其衔接蛋白在衣原体发病机制中的作用，并提出以下具体目标：（1）表征上皮细胞有效感染过程中TLR和CT之间的相互作用和吞噬细胞； (2) 鉴定CT感染过程中上皮细胞和吞噬细胞激活的信号通路； (3) 用 CT 确定原发感染后的细胞变化。 这些研究应该对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产生新的见解。更好地了解该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。