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400万例病例，耗资21.8亿美元。在女性中，这种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，不可逆转的并发症可能是第一症状。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，其中疫苗是一个高度优先事项。抗衣原体疫苗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，确定抗原和介导免疫的免疫效应物。这些研究表明，T细胞介导的免疫反应，包括诱导和募集T辅助型1 （Th1）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对注射上皮细胞释放的趋化因子、募集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以及局部细胞因子分泌的表达和调节。本研究的重点是利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免疫效应物的募集和维持。具体研究将：(a)确定受感染上皮细胞产生的趋化因子，以便将Th1细胞招募到生殖道；(b)确定衣原体感染后表达上调的粘附分子，并在生殖道滞留效应器中发挥作用。本研究结果将有助于更好地了解衣原体感染过程中效应器在生殖器粘膜的募集和滞留的调控机制，从而设计合理的策略来提高衣原体疫苗的疗效和长期保护性免疫。

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.