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

项目总结 性传播感染(STI)是世界范围内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体外数据进行的研究已经产生了大量关于 是什么导致了这些感染，以及这些感染是如何从最初的感染发展到疾病结果的。 最流行的两种性传播疾病，衣原体和淋病是由沙眼衣原体和奈瑟氏菌引起的 淋病。虽然许多毒力因子对这两种病原体都有很好的特性，但还有很多事情要做 了解他们导致盆腔炎、输卵管性不孕和危及生命的异位的途径 怀孕了。现有模型系统的局限性突出表现在对模型的作用认识不足 宫颈阴道微生物区系在淋球菌易感性或对感染的耐药性中的作用 关于沙眼衣原体如何在没有症状的宿主中静默存在的信息，只是有时会再次出现 几年后会导致严重的疾病。拟建的仿生学合作研究中心“结构， 免疫学，微生物组：性传播感染的人类3D仿生宫颈阴道模型 代表了合作工程师和分子微生物学家的开创性努力，以开发出一种新的三种- 适合于研究性传播感染的人宫颈阴道粘膜三维仿生模型 沙眼衣原体和淋病奈瑟菌。该模型忠实地重建了这两种病毒感染的靶组织 病原体包括缺氧环境，宫颈阴道上皮细胞，基础间质 成纤维细胞和由内皮细胞排列的血管系统，通过它免疫细胞可以传递到 被感染的组织。SIM-STI将首次对宫颈阴道微生物区系的作用进行评估 月经周期和合并感染对衣原体和淋球菌致病机制及宿主感染反应的影响。 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， 而且还作为一个临床前平台，用于测试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.