Host-Microbiota Interactions and STI Outcomes

项目摘要 人类性传播感染（STI）的风险取决于多种生物因素，其中 对STI“容许”的宫颈阴道微生物群的出现是突出的。所述微生物组合物 与细菌性阴道病综合征相关的观察结果相似， 通常由高pH（>4.5）、不存在乳杆菌属（Lactobacillus spp.）和一个严格的 和兼性厌氧菌，例如阴道加德纳菌（Gardnerella vagulae）、阴道奇异菌（Atopobium vaginae）、巨球菌属（Megaspaera spp.），以及Prevotella spp.相比之下，典型的“非许可”微生物群由几种乳杆菌中的一种占主导地位， 人类宫颈阴道微生物群的独特特征。非许可性的 子宫颈阴道微生物群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以其天然的形式令人满意地再现了宫颈阴道粘膜， 环境作为实验感染的目标。因此，我们对发病机制的认识， 性传播感染是不完整的，特别是因为它涉及到人类宫颈阴道微生物群的关键作用。我们有 建立了广泛的初步数据，支持项目1的科学前提，并指出， 允许的固有微生物群与宫颈阴道上皮相互作用以建立稳态 阻断性传播感染和/或降低疾病严重程度。相反，允许的微生物群破坏宿主细胞 体内平衡，从而允许STI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 用世界上最流行的性传播感染病原体沙眼衣原体来检验这一假设。项目 1旨在更好地了解宿主-微生物群的相互作用以及它们如何调节C. 沙眼感染在这个项目中，仿生模型将被用来问一些具体的问题， 不同类型的微生物群（允许和非允许）调节上皮细胞功能（目的1）， 与其对衣原体感染的易感性/抗性的关系（目的2）。项目1还将评估 该模型用于检测预防性（目标2）和治疗性（目标3）干预措施的临床前潜力 性病对于这些研究，项目1将充分利用一系列最先进的组学方法， 包括元转录组学和RNA测序，以识别和表征微生物群的改变， 宿主细胞内稳态，宏基因组学和metataxonomics，以确定组成仔细 在仿生模型上重建微生物群或来自人类供体，以及糖组学来分析粘液 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.