Structure, immunity and microbiome: Human 3D biomimetics cervicovaginal models for sexually transmitted infections (SIM-STI)

项目摘要 性传播感染是全世界人类最普遍的感染之一。几十年 使用动物和细胞培养模型以及离体数据的研究已经产生了大量关于 是什么导致这些感染，以及这些感染如何从最初的感染发展到疾病的结果。 两种最普遍的性传播感染，衣原体和淋病，是由沙眼衣原体和奈瑟菌引起的 淋病虽然这两种病原体的许多毒力因子都有很好的特征，但仍有许多问题有待解决。 了解它们导致盆腔炎、输卵管不孕和危及生命的异位妊娠的途径 怀孕现有模型系统的局限性突出表现在对 宫颈阴道微生物群对淋球菌感染的易感性或抵抗力往往相互矛盾 关于如何C。沙眼可能会在宿主体内持续存在，没有症状，只是有时会重新出现， 几年后，引发严重疾病。拟议的仿生学合作研究中心“结构， 免疫，微生物组：用于性传播感染的人类3D仿生宫颈阴道模型 代表了工程师和分子微生物学家合作开发一种新的三- 人宫颈阴道粘膜的三维仿生模型适合于研究由以下因素引起的STI C. trachomatis和N.淋病该模型通过这两种方法忠实地重建了感染的靶组织 病原体，包括缺氧环境、宫颈阴道上皮细胞、下面的基质， 成纤维细胞和由内皮细胞内衬的脉管系统，免疫细胞可以通过所述脉管系统被递送到成纤维细胞。 感染的组织SIM-STI将首次允许评估宫颈阴道微生物群的作用， 月经周期和合并感染对衣原体和淋球菌发病机制和宿主对感染的反应。 这种廉价、易于使用的仿生模型有望解决许多发病机制问题， 而且还可以作为临床前平台，用于测试针对性传播感染的预防和治疗策略。

PROJECT SUMMARY Sexually transmitted infections (STIs) are among the most prevalent infections in humans worldwide. Decades of studies using animal and cell culture models as well as ex vivo data have yielded considerable knowledge on what causes these infections and how these infections proceed from the initial infection to disease outcomes. The two most prevalent STIs, chlamydia and gonorrhea, are caused by Chlamydia trachomatis and Neisseria gonorrhoeae. Although many virulence factors are well characterized for these two pathogens, much remains to be known about their path toward causing pelvic inflammatory disease, tubal infertility and life-threatening ectopic pregnancy. Limitations of existing model systems are highlighted by a poor understanding of the role of the cervicovaginal microbiota in gonococcal susceptibility or resistance to infection and often conflicting available information on how C. trachomatis may persist silently in a host without symptoms to only reappear sometimes years later and cause severe disease. The proposed Biomimetics Cooperative Research Center “Structure, Immunity, Microbiome: Human 3D Biomimetic Cervicovaginal Models for Sexually Transmitted Infections” represents a pioneering effort by collaborating engineers and molecular microbiologists to develop a novel three- dimensional biomimetic model of the human cervicovaginal mucosa amenable to the study of STIs caused by C. trachomatis and N. gonorrhoeae. The model faithfully reconstructs the target tissue of infection by these two pathogens including an anoxic environment, cervicovaginal epithelial cells, the underlying stroma with fibroblasts, and the vasculature lined by endothelial cells, through which immune cells can be delivered to the infected tissue. SIM-STI will allow for the first time an evaluation of the role of the cervicovaginal microbiota, the menstrual cycle and co-infection on chlamydial and gonococcal pathogenesis and host response to infection. This inexpensive, easy to use biomimetic model holds the promise of resolving many questions of pathogenesis, but also to serve as a preclinical platform for testing preventive and therapeutic strategies against STIs.