Host-Microbiota Interactions and Chlamydia Trachomatis Infection Outcomes

项目总结 人类性传播感染(STI)的风险取决于多种生物因素，其中包括 宫颈阴道微生物区系的出现对性传播感染是“允许的”。微生物组成 STI允许的微生物区系的情况类似于与细菌性阴道病综合征相关的观察结果， 通常由高pH值(>4.5)定义的一种状态，即没有乳杆菌。和一系列严格的 以及兼性厌氧菌，如阴道加德纳氏菌、阴道阿托波氏菌、梅加氏杆菌和普雷沃特氏菌 SPP.相比之下，典型的“不允许的”微生物群由几种乳杆菌中的一种主导，一种 人类宫颈阴道微生物区系的独特特征。一种不允许的机制(S) 宫颈阴道微生物区系对性传播感染的保护作用仍然知之甚少，因为没有动物或细胞 迄今为止开发的培养模型系统令人满意地在其自然状态下复制了宫颈阴道粘膜 环境作为实验性感染的目标。因此，我们对其发病机制的认识 性传播感染是不完整的，特别是因为它与人类宫颈阴道微生物区系的关键作用有关。我们有 建立了广泛的初步数据，支持该项目的科学前提，并表示 允许的本土微生物群与宫颈阴道上皮相互作用以建立动态平衡状态 这可以阻止STI和/或降低疾病严重性。相反，允许的微生物群会破坏宿主细胞。 动态平衡，从而使性传播感染得以进展。宫颈阴道黏膜的高级3D器官模型 消除现有模型固有的伦理和生物学限制的方法将被用来检验这一假设， 使用全球最流行的性传播感染药物沙眼衣原体。我们的目标是开发更好的 了解宿主-微生物区系的相互作用以及它们如何调节沙眼衣原体感染的命运。在……里面 该项目将开发种植不同类型重建微生物区系的3D器官类型模型 询问有关不同类型的微生物区系(许可和非许可)如何调节的具体问题 上皮细胞功能(目标1)与其对衣原体感染的易感性/抵抗力的关系(目标2)。 我们还将评估该模型在测试预防性(目标2)和治疗性(目标3)方面的临床前潜力。 对待性传播感染的干预措施。对于这些研究，我们将充分利用最先进的微观和 鉴定和表征微生物区系特异性结构和宿主变化的RNA测序方法 上皮动态平衡和扩大我们对宿主之间的三角关系的理解 微生物群和沙眼衣原体。

PROJECT SUMMARY The risk of sexually transmitted infection (STI) in humans depends on multiple biological factors, among which the occurrence of a cervicovaginal microbiota that is `permissive' to STI stands out. The microbial composition of a STI-permissive microbiota is similar to that observed in association with the syndrome of bacterial vaginosis, a condition that is generally defined by a high pH (>4.5), the absence of Lactobacillus spp. and an array of strict and facultative anaerobes such as Gardnerella vaginalis, Atopobium vaginae, Megasphaera spp., and Prevotella spp. In contrast, a typical `non-permissive' microbiota is dominated by one of several species of Lactobacillus, a unique feature of the human cervicovaginal microbiota. The mechanism(s) by which a non-permissive cervicovaginal microbiota provides protection against STIs remains poorly understood, as no animal or cell culture model system developed to date satisfactorily reproduces the cervicovaginal mucosa in its natural environment as a target for experimental infection. As a consequence, our knowledge of the pathogenesis of STIs is incomplete, particularly as it pertains to the critical role of the human cervicovaginal microbiota. We have established extensive preliminary data that support the scientific premise of this project and states that a non- permissive indigenous microbiota interacts with the cervicovaginal epithelium to establish a homeostatic state that blocks STI and/or reduces disease severity. Conversely, a permissive microbiota disrupts host cell homeostasis, thereby allowing STI to progress. Advanced 3D organotypic models of the cervicovaginal mucosa that eliminate the inherent ethical and biological limitations of existing models will be used to test this hypothesis, using the most prevalent agent of STIs worldwide, Chlamydia trachomatis. We aim to develop a better understanding of the host-microbiota interactions and how they modulate the fate of C. trachomatis infection. In this project, 3D organotypic models colonized with different types of reconstructed microbiota will be exploited to ask specific questions about how different types of microbiota (permissive and non-permissive) modulate epithelial cell functioning (Aim 1) in relationship to their susceptibility/resistance to chlamydial infection (Aim 2). We will also assess the preclinical potential of the model for testing preventive (Aim 2) and therapeutic (Aim 3) interventions against STIs. For these studies, we will leverage the full force of state-of-the-art microscopic and RNA-sequencing methodologies to identify and characterize microbiota specific alterations of structural and host epithelial homeostasis and expand our understanding of the triangular relationship between the host, the microbiota and C. trachomatis.