Unraveling the mechanisms of cell-mediated Chlamydia systemic dissemination.

项目概要/摘要 最近，世卫组织估计，每天有100多万例新的性传播感染。2016年约3.76亿 其中1.27亿是由衣原体引起的。在美国，衣原体仍然是导致 性传播感染，2017年报告了约230万例性传播感染中的170万例。妇女衣原体感染 可能导致宫颈炎、输卵管炎、盆腔炎，引起不孕或危及生命的异位妊娠 怀孕此外，妇女中的衣原体性传播感染与艾滋病毒传播增加有关， 与HPV共感染时宫颈癌的风险增加。尽管付出了巨大的努力， 针对衣原体的粘膜疫苗一直不成功。在小鼠感染模型中，衣原体 从女性生殖道（FRT）传播感染并持续存在于胃肠道（GIT）。GIT 衣原体感染也发生在人类中。在小鼠中，FRT感染小鼠衣原体（Cm）后 分阶段全身传播，首先感染FRT引流髂淋巴结（ILN）， 脾脏和胃肠道厘米传播依赖于迁移的宿主细胞的运输。细胞迁移的抑制 CCR 7-/-小鼠或用FTY 720处理的小鼠减少或消除Cm扩散到脾脏和GIT。 此外，切除脾脏大大减少了GIT的Cm感染。最重要的是， 脾阻碍了上FRT的Cm Ascension，消除了FRT病理。我们假设 脾是Cm增殖容许部位，循环感染细胞有助于Cm扩散到 上FRT。因此，从拟议的工作中获得的知识将提高我们对FRT的理解 免疫生物学，细胞迁移，衣原体发病机制，并将是重要的疫苗的发展 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.