Pathogensis of Chlamydial Infection

沙眼衣原体感染眼生殖器上皮细胞引起致盲性沙眼和性传播疾病（STD）；这些疾病影响着全世界数亿人。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、异位妊娠等。这些疾病的一个病理特征是宿主不能产生足够的保护性免疫反应，导致多次再次感染或持续感染，从而导致病理生理未知的破坏性炎症性疾病。目前沙眼和性病的公共卫生管理是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，这在很大程度上是无效的。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性疾病。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对设计新的有效预防沙眼和性病的疫苗具有重要意义。为此，我们利用雌性小鼠泌尿生殖道感染模型，重点研究了两种衣原体毒力因子；(i)沙眼衣原体包膜蛋白CT135， （ii）沙眼衣原体质粒。我们发现CT135通过将外膜脂蛋白（一种病原体相关的分子模式分子）从衣原体包裹体输出到宿主细胞质中来逃避宿主先天免疫。CT135输出脂蛋白特异性靶向并激活吞噬细胞的MyD88非规范炎性体途径，导致il - 1- α和il - 1- β的分泌，随后驱动破坏性的炎性输卵管病理。此外，我们发现衣原体质粒在女性生殖道持续感染的建立中起作用。质粒基因蛋白3和4是建立持续感染所必需的。未来的研究将设计经过基因修饰的沙眼衣原体疫苗菌株，使其具有突变失活的CT135并被质粒治愈。这些菌株将作为减毒活疫苗进行试验，以利用小鼠生殖道模型预防衣原体性传播疾病。

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.