Unraveling mechanisms by which cervicovaginal microbiota can promote or prevent cervical remodeling and preterm birth

揭示宫颈阴道微生物群促进或预防宫颈重塑和早产的机制

• 批准号: 10397425
• 负责人: MICHAL Aviva ELOVITZ
• 金额: $ 48.03万
• 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: 2020-08-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397425
• 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; Mucous Membrane; Mus; Pathogenesis; Placenta; Pregnancy; Pregnant Women; Premature Birth; Preventive; Process; Production; Proteomics; 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

Summary: 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), 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.

摘要：每年有1500万婴儿早产。超过75%的早产（PTBs）被命名