Pathogensis of Chlamydial Infection

沙眼衣原体感染眼球生殖器上皮细胞会导致致盲沙眼和性传播疾病(STD)，这些疾病影响着全世界数亿人。女性感染有严重的感染后后遗症，如盆腔炎、输卵管因素不孕、异位妊娠等。这些疾病的一个病因学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，从而导致未知病理生理的破坏性炎症性疾病。目前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，这些治疗在很大程度上无效。沙眼和衣原体性病的有效控制需要疫苗。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，这种防御允许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对于设计预防沙眼和性病的新的有效疫苗将是重要的。为此，我们使用了一种雌性小鼠泌尿生殖道感染模型，重点研究了沙眼衣原体的两种毒力因子：(I)沙眼衣原体质粒，(Ii)沙眼衣原体包涵膜蛋白CT135。我们发现质粒基因蛋白Pgp3是建立小鼠女性生殖道持续感染所必需的。我们进一步确定了Pgp3作为天然免疫抑制因子的致病机制。我们发现，CT135通过激活NLRP3炎性小体杀死管腔中性粒细胞，在建立持续的子宫上皮细胞感染中是必不可少的。CT135通过输出中性粒细胞衣原体感染流产时产生的衣原体外膜脂蛋白片段，在炎症小体激活中发挥作用。输出的衣原体脂蛋白片段结合包涵膜相关的TLR2，导致MyD88信号转导和NLRP3炎性染色体的激活。这一过程导致中性粒细胞死亡和IL-1-β的分泌。根据这些发现，CT135具有逃避中性粒细胞宿主防御的功能。有趣的是，这种宿主防御机制共同驱动了生殖道髓系介导的免疫病理。未来的研究将设计沙眼衣原体疫苗株，这些疫苗株已被基因改造为突变失活的CT135，并治愈了该质粒。这些菌株将作为减毒活疫苗进行测试，以预防衣原体STD，使用雌性小鼠生殖道模型。

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 plasmid, and (ii) the C. trachomatis inclusion membrane protein CT135. We found the plasmid gene protein Pgp3 is required to establish persistent infection of the mouse female genital tract. We further identified the pathogenic mechanism of Pgp3 as an inhibitor of innate immunity anti-microbial peptides. We found that CT135 is essential for establishing continuous infection of uterine epithelial cells by killing luminal neutrophils by activating the NLRP3 inflammosome. CT135 was shown to function in inflammosome activation by exporting chlamydial outer membrane lipoprotein fragments generated during abortive chlamydial infection of neutrophils. Exported chlamydial lipoprotein fragments bound inclusion membrane associated TLR2 resulting in MyD88 signaling and activation of the NLRP3 inflammosome. This processes resulted in neutrophil death and secretion of IL1-beta. We conclude from these findings that CT135 functions to evade neutrophil host defense. Interestingly, this host defense mechanism conjointly drives genital tract myeloid mediated immunopathology. 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 female mouse genital tract model.