Six new Chlamydia epitopes

描述（由申请人提供）：沙眼衣原体是发达国家最常见的细菌性传播疾病，在青少年和年轻人中患病率接近10%。在妇女中，沙眼衣原体感染上升到上生殖道，造成疤痕，导致不孕和异位妊娠。抗生素治疗在解决该疾病的流行方面无效，因此开发保护性疫苗是解决这种常见感染的合理方法。来自C. muridarum小鼠模型的现有数据显示，CD4 T细胞克隆在体外控制上皮细胞中衣原体复制的能力与其在体内保护生殖道的能力之间存在相关性。同样，在C. muridarum模型中的现有疫苗数据表明，并非所有衣原体抗原都能诱导保护性免疫。开发保护性衣原体疫苗的主要挑战是确定约900种衣原体蛋白中哪一种能够诱导保护性免疫。基于现有数据，我们假设保护性表位将在衣原体蛋白亚群中发现，这些蛋白被感染的上皮细胞加工和呈递，产生CD4 T细胞反应，能够控制衣原体在上皮细胞中的复制。CD4 T细胞克隆识别和控制muridarum在上皮细胞中的复制是鉴定候选疫苗抗原的逻辑工具。我们建议利用我们独特的上皮细胞系，现有的衣原体特异性CD4 T细胞克隆，以及产生衣原体突变体和重组体的新技术专长来实现以下具体目标：#1利用重组和突变的muridarum文库结合基因组测序鉴定6个新的“上皮”CD4表位源蛋白；#2研究感染上皮细胞上表位丰度的作用，作为CD4 T细胞介导的muridarum在上皮细胞复制控制的参数；#3研究每个鉴定的表位源蛋白诱导保护的能力

DESCRIPTION (provided by applicant): Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the developed world with a prevalence approaching 10% in adolescents and young adults. In women C. trachomatis infections ascend into the upper reproductive tract causing scarring that results in infertility and ectopic pregnancy. Antibiotic therapy has been ineffective in addressing the prevalence of the disease making development of a protective vaccine a logical approach to address this common infection. Existing data from the C. muridarum mouse model shows a correlation between a CD4 T cell clones ability to control replication of Chlamydia in epithelial cells in vitro and its ability to protect the reproductive tract in vivo. Similarly, existing vaccine data in the C. muridarum model has shown that not all Chlamydia antigens induce protective immunity. The major challenge for development of a protective Chlamydia vaccine is identifying which of the ~900 Chlamydia proteins is capable of inducing protective immunity. We hypothesize based on existing data that the protective epitopes will be found in the subset of Chlamydia proteins that are processed and presented by infected epithelial cells, generating a CD4 T cell response capable of controlling Chlamydia replication in epithelial cells. CD4 T cell clones that recognize and control C. muridarum replication in epithelial cells are logical tools for identifying candidate vaccine antigens. We propose using our unique epithelial cell lines, existing panel of Chlamdydia- specific CD4 T cell clones, and novel technologic expertise in generating Chlamydia mutants and recombinants to accomplish the following specific aims: #1 to identify six new "epithelial" CD4 epitope-source proteins using recombinant and mutant libraries of C. muridarum combined with genomic sequencing, #2 to investigate the role of epitope abundance on infected epithelial cells as a parameter for CD4 T cell-mediated control of C. muridarum replication in epithelial cells, #3 to investigate the ability of each identified epitope source protein to induce protective vaccine immunity in the C. muridarum mouse model.