CHEMOKINE REGULATION OF MUCOSAL IMMUNITY AGAINST GENITAL CHLAMYDIAL INFECTION

由专性细胞内细菌沙眼衣原体引起的生殖器感染是美国最常见的细菌性性传播疾病（STD），每年有400万例，耗资21.8亿美元。在妇女感染可导致严重的并发症，包括盆腔炎，异位妊娠和不孕症。许多感染是无症状的，不可逆的并发症可能是最初的症状。衣原体对人类生殖、福祉和国家预算构成潜在威胁，这一明显的关切加强了对干预和预防战略的研究，其中疫苗是一个高度优先事项。抗衣原体疫苗研究包括使用动物模型研究疾病的发病机理和免疫生物学，并确定介导免疫的抗原和免疫效应物。这些研究表明，T细胞介导的免疫应答，包括诱导和募集T辅助1型（Th 1）细胞进入生殖器粘膜，对衣原体免疫至关重要。这些因素可能会影响生殖器粘膜的表达和调节注射的上皮细胞释放的趋化因子，募集的白细胞上的趋化因子受体，参与生殖器粘膜淋巴上皮相互作用的粘附分子，和局部细胞因子分泌。该建议的重点是使用新的体外和体内模型的衣原体感染和分子和生物化学技术，以调查招聘和维护生殖器粘膜感染后的免疫效应。具体研究将：（a）鉴定由受感染的上皮细胞加工的趋化因子，用于将Th 1细胞募集到生殖道中;和（B）鉴定在衣原体感染后上调并在生殖道中效应物的保留中起作用的某些粘附分子。本研究的结果将有助于更好地了解衣原体感染期间生殖器粘膜中效应子招募和保留的调节机制，这可能导致设计合理的策略以提高衣原体疫苗的有效性和长期保护性免疫。

Genital infection by the obligate intracellular bacterium, Chlamydia trachomatis, is the most common bacterial sexually transmitted disease (STD) in the United States, with four million annual cases that cost $2.18 billion. In women the infection can lead to serious complications, including pelvic inflammatory disease, ectopic pregnancy and infertility. Many of the infections are asymptomatic and irreversible complications may be the first symptoms. The obvious concern that Chlamydia poses a potential threat to human reproduction, well-being and national budgets has intensified research on intervention and prevention strategies, of which a vaccine is a high priority. Anti-chlamydial vaccine research include the use of animal models for studying the pathogenesis and immunobiology of the disease, and defining antigens and immune effectors mediating immunity. These studies have shown that T cell- mediated immune responses, involving the induction and recruitment of T helper type 1 (Th1) cells into the genital mucosa is crucial for chlamydial immunity. Such factors would likely influence the genital mucosal expression and regulation of chemokines released by injected epithelial cells, chemokine receptors on recruited leukocytes, adhesion molecules involved in genital mucosal lymphoepithelial interactions, and local cytokine secretion. The focus of this proposal is to use novel in vitro and in vivo models of chlamydial infection and molecular and biochemical techniques to investigate the recruitment and maintenance of immune effectors in the genital mucosa following an infection. Specific studies will: (a) identify the chemokines elaborated by infected epithelial cells, for recruiting Th1 cells into the genital tract; and (b) identify certain adhesion molecules that are up-regulated after chlamydial infection and play a role in the retention of effectors in the genital tract. The results from this study will contribute to a better understanding of the regulatory mechanisms of effector recruitment and retention in the genital mucosa during chlamydial infection, which may lead to the designing of rational strategies to enhance the efficacy and long-term protective immunity of a chlamydial vaccine.