Unraveling the mechanisms of cell-mediated Chlamydia systemic dissemination.

项目摘要/摘要 最近，世卫组织估计，每天有100多万新的性传播感染。2016年约3.76亿 新的性传播感染中，有1.27亿人是由衣原体引起的。在美国，衣原体感染仍然是导致 性传播感染，2017年报告了约230万例性传播感染病例。女性衣原体感染 可能导致子宫颈炎、输卵管炎、盆腔炎，导致不孕症或危及生命的异位 怀孕了。此外，女性衣原体感染与艾滋病毒和艾滋病的传播增加有关 当混合感染HPV时，患宫颈癌的风险增加。尽管付出了巨大的努力，但 针对衣原体的粘膜疫苗一直未获成功。在感染的小鼠模型中，衣原体 从女性生殖道(FRT)传播，感染并持续在胃肠道(GIT)。Git 衣原体感染也发生在人类身上。在小鼠中，在FRT感染后，鼠衣原体(Cm) 系统地分阶段传播，首先感染FRT引流的髂骨淋巴结(ILN)，然后 还有脾脏和下巴。CM的传播依赖于迁移宿主细胞的携带。细胞迁移的抑制作用 CCR7-/-小鼠或用FTY720治疗的小鼠减少或阻止CM扩散到脾和胃肠道。 此外，切除脾大大减少了胃肠道的CM感染。最重要的是，删除 脾阻碍了上FRT的CM上升，并废除了FRT的病理。我们假设 脾是允许CM增殖的地方，循环中的感染细胞有助于CM传播到 上档FRT。因此，从拟议的工作中获得的知识将提高我们对首次公开募股的理解 免疫生物学、细胞迁移、衣原体致病机制，并将对疫苗的开发具有重要意义 以及针对这种病原体的治疗方法。

PROJECT SUMMARY/ABSTRACT Recently WHO estimated that more than 1 million new STIs are acquired daily. In 2016 of about 376 million new STIs, 127 million were caused by Chlamydia. In the US, Chlamydia continues to be a leading cause of STIs, with 1.7 million cases of approximately 2.3 million STIs reported in 2017. Chlamydial infections in women may result in cervicitis, salpingitis, pelvic inflammatory disease, causing infertility or life-threatening ectopic pregnancy. Moreover, chlamydial STIs in women are associated with increased transmission of HIV and an increased risk of cervical cancer when co-infected with HPV. In spite of great efforts, the development of mucosal vaccines that target Chlamydia has been unsuccessful. In the mouse model of infection, Chlamydia spreads from the female reproductive tract (FRT) to infect and persist in the gastro-intestinal tract (GIT). GIT infections with Chlamydia also occur in humans. In mice, following FRT infection Chlamydia muridarum (Cm) disseminates systemically in stages, by first infecting the FRT-draining iliac lymph nodes (ILNs), then the spleen, and the GIT. Cm dissemination relies on carriage by migrating host cells. Inhibition of cell migration in CCR7-/- mice or in mice treated with FTY720 diminishes or abrogates Cm spread to the spleen and the GIT. Moreover, removal of the spleen drastically reduces Cm infection of the GIT. Most importantly, removal of the spleen hinders Cm ascension in the upper FRT and abrogates the FRT pathology. We hypothesize that the spleen is a permissive site for Cm proliferation and that circulating infected cells contribute to Cm spread to the upper FRT. Therefore, the knowledge gained from the proposed work will improve our understanding of FRT immunobiology, cell migration, Chlamydia pathogenesis, and will be important for the development of vaccines and therapies to target this pathogen.