THE VAGINAL MICROBIOME, MATERNAL RESPONSE, AND PRETERM BIRTH

摘要 据估计，全世界每年发生1300万例早产（PTB），PTB是最常见的一种。 是新生儿发病率和死亡率的重要促成因素。早产的潜在机制 出生情况不明阻碍了有效预测和预防战略的制定。PTB是 与局部和远处感染有关，最近的数据表明， 怀孕与随后的早产有关。病毒感染的表现不同， 怀孕，与常见的病毒感染，如水痘和流感，造成更严重的 怀孕期间的疾病和宫颈癌的致病病毒人乳头瘤病毒， 与PTB风险增加2倍相关。然而，阴道病毒的综合评估 在怀孕期间，社区没有进行。最后，虽然产妇炎症是 PTB的主要触发因素之一，炎性信号的精确星座尚不清楚。我们 我认为，单独研究微生物群落或宿主反应是不完整的， 结合将导致适当和不适当的微生物母体生物学的精确定义 为肺结核这个老问题提供了新的线索 我们的中心假设是，早产可以通过三个标准的组合来估计： 阴道细菌群落、阴道真核病毒群落和母体 炎症反应。我们有一个跨学科的团队，包括围产期专家， 流行病学家、病毒学家和基因组学信息学专家，利用 位于圣路易斯的华盛顿大学麦克唐纳基因组研究所， 生物标本和临床数据基础设施，以及高PTB负担的种族多样性患者 来验证这个新的假设。 本项目的目的是：1）确定阴道中细菌和病毒群落的能力 以及它们随时间的动态变化来预测早产2）确定宿主炎症的能力 在微生物群落的背景下，阴道中的反应可以预测早产。拟议 这项研究是创新的，首次全面表征真核阴道病毒组， 同时与阴道细菌群落和纵向捕获母体反应 这些社区。我们采用了有效的研究设计，一个完善的研究， 基础设施和著名的基因组测序专业知识，以测试一个生理上合理的，但 未经调查的范例，细菌和病毒群落与母体宿主一致， 反应可以预测PTB。

ABSTRACT An estimated 13 million preterm births (PTBs) occur annually worldwide, and PTB is the single most significant contributing factor to neonatal morbidity and mortality. Mechanisms underlying preterm birth are unknown hampering development of effective prediction and prevention strategies. PTB is linked to local and distant infections and recent data suggests that vaginal bacterial microbiome early in pregnancy is associated with subsequent preterm birth. Viral infections behave differently during pregnancy, with common viral infections such as varicella and influenza causing much more severe disease during pregnancy and human papillomavirus, the causative virus in cervical cancer, associated with a 2-fold increased risk for PTB. However, comprehensive assessment of vaginal viral communities during pregnancy has not been performed. Lastly, although maternal inflammation is one of the leading triggers for PTB the precise constellation of inflammatory signals is not known. We propose that examining microbial communities or host response alone is incomplete, but that their combination will lead to refined definitions of appropriate and inappropriate microbe-maternal biology and shed new light on the old problem of PTB. Our central hypothesis is that preterm birth can be estimated by a combination of three criteria: vaginal bacterial communities, vaginal eukaryotic viral communities, and maternal inflammatory response. We have an interdisciplinary team assembled including perinatologists, epidemiologists, virologists, and genomics informatics experts, leveraging the unique capabilities of the McDonnell Genome Institute at Washington University in St. Louis, a well-established pregnancy bio-specimen and clinical data infrastructure, and a high-PTB burdened racially diverse patient population to test this novel hypothesis. The aims of this project are: 1) Determine the ability of bacterial and viral communities in the vagina and their dynamics over time to predict preterm birth 2) Determine the ability of the host inflammatory response in the vagina in the context of microbial communities to predict preterm birth. The proposed research is innovative, for the first time, comprehensively characterizing the eukaryotic vaginal virome simultaneously with vaginal bacterial communities and longitudinally capturing the maternal response to these communities. We employ an efficient study design, a well-established research infrastructure, and renowned genome sequencing expertise to test a physiologically plausible but uninvestigated paradigm that bacterial and viral communities in concert with the maternal host response can predict PTB.