Deciphering the Role of Vaginal Microbes in Preterm birth

解读阴道微生物在早产中的作用

• 批准号: 10432076
• 负责人: MICHAL Aviva ELOVITZ
• 金额: $ 49.91万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432076
• 关键词: Address; Automobile Driving; Bacteria; Biological Process; Biomechanics; Birth; Cancer Biology; Cervical; Cervix Uteri; Epithelial; Epithelial Cells; Etiology; Extracellular Matrix; Fetal Membranes; Fibrosis; Fostering; Gardnerella vaginalis; Gelatinase B; Germ-Free; Goals; Human; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Knowledge; Lead; Measures; Mesenchymal; Metabolic; Microbe; Mobiluncus mulieris; Mucous Membrane; Mus; Pathogenesis; Pregnancy; Pregnant Women; Premature Birth; Preventive; Process; Production; Proteomics; Reporting; Reproducibility; Role; Scientist; Series; Structure; Study models; Techniques; Term Birth; Testing; Therapeutic; Time; Tissues; Uterus; Vagina; Work; cervical remodeling; cervicovaginal; clinically relevant; cohort; commensal bacteria; experimental study; fetal; in vivo; in vivo Model; innovation; insight; intraamniotic infection; metabolic profile; microbial community; microbiota; mouse model; multidisciplinary; new therapeutic target; novel; pregnant; premature; prevent; protease E; reproductive tract; response; successful intervention; therapeutic target; uterine contractility; vaginal infection

Every year, 15 million babies are born premature. Over 75% of preterm births (PTBs) are termed spontaneous (sPTB) resulting in parturition at early gestational time points without clear causes. Our lack of understanding of the mechanisms and overall pathogenesis that promotes sPTB results in limited successful interventions. While uterine contractility and cervical remodeling appear to be obligatory processes in parturition, premature triggers of these processes remain poorly elucidated. Recent studies reveal close associations between cervicovaginal (CV) microbial communities and the occurrence of sPTB. In particular, we recently studied a cohort of 2000 pregnant women and assessed the CV microbial communities, metabolic and immune responses early in pregnancy, providing strong evidence that colonization with specific bacterial taxa, specific metabolic profiles, and local immune responses were strongly associated with sPTB. However, to develop preventive or therapeutic strategies, understanding the cause of sPTB is essential. We speculate that interplay between the CV microbial communities, local immune response and the cervical and vaginal epithelial barriers induce premature cervical remodeling and initiate sPTB. The overall goal of this study is to define how specific CV bacteria interact with vaginal and epithelial cells in clinically relevant in vitro and in vivo models and to understand how those interactions modify tissue remodeling and biomechanics of the pregnant cervix, driving sPTB. We propose a process whereby bacterial taxa that are highly associated with sPTB in humans provoke exfoliation of the vaginal epithelium. This process promotes epithelial-mesenchymal transition (EMT) from both vaginal and cervical epithelial cells. While activation of EMT prevents the ascension of these bacteria, a tradeoff is that EMT fosters breakdown of the extracellular matrix in the cervical tissue, triggering premature cervical remodeling and sPTB. Therefore, our central hypothesis is that specific bacteria, such as Gardnerella vaginalis (G.vaginalis) and Mobiluncus mulieris (M. Mulieris), promote EMT of the vaginal and cervical epithelial barrier which alters the structure and function of the pregnant cervix, leading to sPTB, even in the absence of ascending infection (above the cervix). This paradigm-shifting hypothesis will be tested through a series of in vitro and in vivo experiments. This proposal will first address whether ascension of bacteria into the uterus is actually necessary for PTB to occur; these studies have the potential to reframe our scientific and therapeutic approach to PTB. We will then demonstrate how bacteria induce EMT in CV epithelial barriers and how EMT might promote premature cervical remodeling. Unique to this proposal, we will provide quantitative assessment of the pregnant cervix, in terms of structure and function, in a mouse model of PTB. A multidisciplinary team adds rigor to our work by applying novel concepts and techniques to the study of sPTB. These studies will provide insight as to new and focused therapeutic targets to limit or prevent sPTB and will significantly advance this field.

每年有1500万婴儿早产。超过75%的早产（PTB）被称为自发性 （sPTB）导致在妊娠早期时间点分娩而没有明确的原因。我们缺乏理解 促进sPTB的机制和总体发病机制的研究导致有限的成功干预。 虽然子宫收缩和宫颈重塑似乎是分娩过程中的强制性过程， 这些过程的触发因素仍不清楚。最近的研究表明， 宫颈阴道（CV）微生物群落和sPTB的发生。特别是，我们最近研究了 队列的2000名孕妇，并评估了CV微生物群落，代谢和免疫 反应在怀孕早期，提供了强有力的证据表明，殖民与特定的细菌类群，具体 代谢谱和局部免疫应答与sPTB强烈相关。但是，要发展 预防或治疗策略，了解sPTB的原因是必不可少的。我们推测相互作用 CV微生物群落、局部免疫反应与宫颈和阴道上皮屏障之间的关系 诱导过早的宫颈重塑并引发sPTB。这项研究的总体目标是确定如何具体 CV细菌在临床相关的体外和体内模型中与阴道和上皮细胞相互作用， 了解这些相互作用如何改变妊娠子宫颈的组织重塑和生物力学， sPTB。我们提出了一个过程，即与人类sPTB高度相关的细菌类群引起 阴道上皮脱落。这一过程促进上皮间充质转化（EMT）， 阴道和宫颈上皮细胞。虽然EMT的激活阻止了这些细菌的Ascension， EMT的代价是促进宫颈组织中细胞外基质的分解， 宫颈重塑和sPTB。因此，我们的中心假设是，特定的细菌，如 Gardnerella vagularis（G. vagularis）和Mobiluncus mulieris（M. Mulieris），促进阴道的EMT， 宫颈上皮屏障改变妊娠宫颈的结构和功能，甚至导致sPTB 在没有上行感染的情况下（宫颈以上）。这一范式转换假说将得到检验 通过一系列的体外和体内实验。这一建议将首先解决是否Ascension 细菌进入子宫实际上是PTB发生的必要条件;这些研究有可能重新构建我们的研究框架。 对肺结核采取科学和治疗方法。然后，我们将展示细菌如何诱导CV上皮细胞中的EMT 以及EMT如何促进过早的宫颈重塑。本提案的独特之处在于，我们将提供 在PTB小鼠模型中对妊娠子宫颈的结构和功能进行定量评估。一 多学科团队通过将新的概念和技术应用于sPTB的研究，为我们的工作增添了严谨性。 这些研究将为限制或预防sPTB提供新的和集中的治疗靶点， 大大推进了这一领域。