Host-Microbiota Interactions and STI 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，支持项目1的科学前提，并表示非 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。创新和先进的3D仿生模型 消除现有模型固有的伦理和生物学限制的宫颈阴道粘膜将是 用全世界最流行的性传播感染病原体沙眼衣原体来验证这一假设。项目 1旨在更好地了解寄主-微生物区系的相互作用以及它们如何调节C. 沙眼病毒感染。在这个项目中，仿生模型将被用来问一些具体的问题： 不同类型的微生物区系(许可和非许可)调节上皮细胞功能(目标1) 与他们对衣原体感染的易感性/抵抗力的关系(目标2)。项目1还将评估 用于检测预防(目标2)和治疗性(目标3)干预措施的模型的临床前潜力 性传播疾病。对于这些研究，项目1将充分利用一系列最先进的组学方法， 包括后转录组学和RNA测序，以识别和表征微生物区系和 宿主细胞动态平衡、元基因组学和元基因组学仔细定义成分 在仿生模型上重建的微生物区系或来自人类捐赠者的微生物区系，以及分析粘液的糖组 结构特征。

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 Project 1 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. Innovative and advanced 3D biomimetic 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. Project 1 aims to develop a better understand of the host-microbiota interactions and how they modulate the fate of C. trachomatis infection. In this project, the biomimetic models 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). Project 1 will also assess the preclinical potential of the model for testing preventive (Aim 2) and therapeutic (Aim 3) interventions against STIs. For these studies, Project 1 will leverage the full force of an array of state-of-the-art omics methodologies, including metatranscriptomics and RNA-sequencing to identify and characterize alterations of microbiota and host cellular homeostasis, metagenomics and metataxonomics to define the composition of carefully reconstructed microbiota or from human donors on the biomimetic models, and glycomics to analyze mucus structural features.