Pathogensis of Chlamydial Infection

眼生殖器上皮细胞的沙眼衣原体感染可导致致盲性沙眼和性传播疾病（STD）;这些疾病影响着全球数亿人。 女性感染后有严重的感染后遗症，如盆腔炎、输卵管因素不孕、宫外孕等。 这些疾病的一个特征是宿主不能产生足够的保护性免疫应答，导致多次再感染或持续感染，从而导致病理生理学未知的破坏性炎症性疾病。 目前对沙眼和性病的公共卫生管理分别基于大规模药物治疗或积极的诊断筛查和抗生素治疗;不幸的是，这在很大程度上无效。 有效控制沙眼和衣原体性传播疾病需要疫苗。 我们工作的总体目标是了解衣原体逃避宿主防御的致病机制，从而建立慢性感染和破坏性炎症疾病。 我们的逻辑是，更好地了解衣原体感染和疾病的病理生物学将是重要的设计新的有效的疫苗，用于预防沙眼和性病。 为此，我们使用了一种雌性小鼠泌尿生殖道感染模型，并将我们的调查集中在两个衣原体毒力因子的研究上：（i）衣原体毒力因子;沙眼衣原体包涵体膜蛋白CT 135;沙眼质粒 我们发现CT 135的功能是通过将外膜脂蛋白（一种病原体相关的分子模式分子）从衣原体包涵体输出到宿主细胞质中来逃避宿主的先天免疫。 CT 135输出的脂蛋白特异性靶向并激活吞噬细胞的MyD 88非经典炎性体途径，导致IL 1-α和IL 1-β的分泌，其随后驱动破坏性炎性输卵管病理学。 此外，我们发现衣原体质粒在建立女性生殖道持续感染中发挥作用。 质粒基因蛋白3和4被认为是必不可少的建立持续感染。 未来的研究将设计C.沙眼疫苗株已被遗传修饰为突变失活的CT 135并消除了质粒。 这些菌株将作为减毒活疫苗使用小鼠生殖道模型进行检测，以预防衣原体STD。

Chlamydia trachomatis infection of oculogenital epithelial cells causes blinding trachoma and sexually transmitted disease (STD); diseases that affect hundreds of millions of people world-wide. Infection of women has serious post-infection sequalae such as pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. A pathognomonic feature of these diseases is the inability of the host to generate an adequate protective immune response resulting in multiple episodes of re-infection or persistent infection that leads to damaging inflammatory disease of unknown pathophysiology. Current public health management of trachoma and STD is based on mass drug treatment or aggressive diagnostic screening and antibiotic treatment; respectively, that unfortunately have been largely ineffective. Effective control of trachoma and chlamydial STD requires a vaccine. The overall goal of our work is to understand the pathogenic mechanisms by which chlamydia evade host defenses that allow for the establishment of chronic infection and damaging inflammatory disease. Our logic is that a better understanding of the pathobiology of chlamydial infection and disease will be important to the design of new effective vaccines for the prevention of trachoma and STD. To this end, we have used a female mouse model of urogenital tract infection and focused our investigations on the study of two chlamydial virulence factors; (i) the C. trachomatis inclusion membrane protein CT135, and (ii) the C. trachomatis plasmid. We found CT135 functions in the evasion of host innate immunity by exporting outer membrane lipoprotein, a pathogen associated molecular pattern molecule, from the chlamydial inclusion to the host cytosol. CT135 exported lipoprotein specifically targets and activates the MyD88 non-canonical inflammasome pathway of phagocytes resulting in the secretion of IL1-alpha and IL1-beta that subsequently drives damaging inflammatory oviduct pathology. Moreover, we found that the chlamydial plasmid functions in the establishment of persistent infection of the female genital tract. Plasmid gene proteins 3 and 4 were found to be essential in establishing persistent infection. Future studies will design C. trachomatis vaccine strains that have been genetically modified to mutationally inactive CT135 and cured of the plasmid. These strains will be tested as live-attenuated vaccines to prevent chlamydial STD using the mouse genital tract model.