Host-Microbiota Interactions and STI Outcomes

宿主-微生物群相互作用和性传播感染结果

基本信息

批准号：
10596513
负责人：
Jacques Ravel
金额：
$ 13.66万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-20 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596513
关键词：
3-Dimensional Anaerobic Bacteria Animals Atopobium vaginae Bacterial Vaginosis Biological Biological Factors Biological Models Biomimetics Cell Culture Techniques Cell physiology Cells Chlamydia Infections Chlamydia trachomatis Complex Data Disease Progression Environment Epithelial Cells Epithelium Ethics Gardnerella vaginalis Genetic Transcription Goals Histologic Histology Homeostasis Human Immune response Immunity Immunologics Indigenous Infection Intervention Knowledge Knowledge acquisition Lactobacillus Metagenomics Methodology Modeling Mucous Membrane Mucous body substance Outcome Pathogenesis Pattern Preclinical Testing Predisposition Preventive Prevotella Process Property Research Resistance Risk Role Seminal fluid Series Severity of illness Sexually Transmitted Agents Sexually Transmitted Diseases Structure Syndrome Testing Therapeutic Woman cervicovaginal comparative host microbiota immune function in vivo innovation metabolomics metatranscriptomics microbial composition microbiome microbiota microorganism permissiveness pre-clinical assessment prevent programs restoration tool transcriptome sequencing vaginal microbiota

项目摘要

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.

项目概要人类感染性传播感染（STI）的风险取决于多种生物学因素，其中 “允许”性传播感染的宫颈阴道微生物群的出现非常引人注目。允许性传播感染的微生物群与细菌性阴道病综合征相关的微生物群相似，这种情况通常由高 pH 值 (>4.5)、缺乏乳酸菌和一系列严格的条件来定义。以及兼性厌氧菌，例如阴道加德纳菌、阴道阿托波菌、巨球菌属和普雷沃菌相比之下，典型的“非允许”微生物群以几种乳酸菌中的一种为主。人类宫颈阴道微生物群的独特特征。子宫颈阴道微生物群对性传播感染的保护作用仍知之甚少，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再现了宫颈阴道粘膜的自然状态因此，我们对感染的发病机制的了解。性传播感染是不完整的，特别是因为它涉及人类宫颈阴道微生物群的关键作用。建立了广泛的初步数据来支持项目 1 的科学前提，并指出非允许的本土微生物群与宫颈阴道上皮相互作用以建立稳态阻止性传播感染和/或疾病严重程度降低，允许的微生物群会破坏宿主细胞。稳态，从而使 STI 的创新和先进的 3D 仿生模型得以发展。消除现有模型固有的伦理和生物学局限性的子宫颈阴道粘膜将被用于检验这一假设，使用了世界上最流行的性传播感染病原体——沙眼衣原体项目。 1 旨在更好地了解宿主与微生物群的相互作用以及它们如何调节艰难梭菌的命运。在该项目中，将利用仿生模型来询问有关沙眼感染的具体问题。不同类型的微生物群（允许的和非允许的）调节上皮细胞功能（目标 1）与衣原体感染的易感性/抵抗力的关系（目标 2）。该模型用于测试预防性（目标 2）和治疗性（目标 3）干预措施的临床前潜力对于这些性传播感染研究，项目 1 将充分利用一系列最先进的组学方法，包括宏转录组学和 RNA 测序，以识别和表征微生物群的变化宿主细胞稳态、宏基因组学和元分类学来仔细定义在仿生模型上重建微生物群或来自人类捐赠者，并使用糖组学来分析粘液结构特点。