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传播疾病(STD)，每年有400万例，造成21.8亿美元的损失。在女性中，这种感染可能会导致严重的并发症，包括盆腔炎、宫外孕和不孕。许多感染是无症状的，不可逆转的并发症可能是首发症状。对衣原体对人类生殖、福祉和国家预算构成潜在威胁的明显关切加强了对干预和预防战略的研究，其中疫苗是高度优先事项。抗衣原体疫苗的研究包括利用动物模型研究该病的发病机制和免疫生物学，以及确定介导免疫的抗原和免疫效应物。这些研究表明，T细胞介导的免疫反应，包括T辅助细胞1型(Th1)细胞的诱导和募集到生殖器粘膜，是衣原体免疫的关键。这些因素可能会影响生殖器粘膜的表达和对注射的上皮细胞释放的趋化因子的调节、招募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黏附分子以及局部细胞因子的分泌。这项建议的重点是使用新的体外和体内衣原体感染模型以及分子和生化技术来研究感染后生殖器粘膜中免疫效应物的招募和维持。具体研究将：(A)确定受感染的上皮细胞为将Th1细胞招募到生殖道而精心设计的趋化因子；(B)确定在衣原体感染后上调并在生殖道保留效应器方面发挥作用的某些黏附分子。本研究的结果将有助于更好地理解衣原体感染时效应器在生殖器粘膜中募集和滞留的调节机制，从而可能导致设计合理的策略来提高衣原体疫苗的效力和长期保护性免疫。

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.