THE VAGINAL MICROBIOME, MATERNAL RESPONSE, AND PRETERM BIRTH

摘要 据估计，全世界每年有1300万早产儿，其中早产儿最多。 导致新生儿发病率和死亡率的重要因素。早产的发病机制 出生是未知的，阻碍了有效预测和预防战略的发展。PTB是 与局部和远程感染有关，最近的数据表明，阴道细菌微生物群早期 怀孕与随后的早产有关。病毒感染的表现不同于 妊娠，常见的病毒感染，如水痘和流感，导致更严重 孕期疾病和导致宫颈癌的人类乳头瘤病毒， 与肺结核的风险增加2倍相关。然而，阴道病毒的综合评估 还没有在怀孕期间开展社区活动。最后，尽管母体炎症是 炎症信号的准确组合是引发肺结核的主要诱因之一，但目前尚不清楚。我们 建议单独研究微生物群落或宿主的反应是不完整的，但他们的 结合将导致对适当和不适当的微生物-母体生物学的精确定义 并为结核病的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。我们有一个包括围产期医生在内的跨学科团队， 流行病学家、病毒学家和基因组信息学专家，利用 圣路易斯华盛顿大学麦克唐纳基因组研究所，一次公认的怀孕 生物标本和临床数据基础设施，以及一个高肺结核负担的种族多样性患者 来检验这一新的假设。 该项目的目标是：1)确定阴道中细菌和病毒群落的能力 随着时间的推移，它们预测早产的动态变化决定了宿主发炎的能力 在阴道微生物群落的背景下预测早产的反应。建议数 这项研究具有创新性，首次全面描述了真核阴道病毒的特征 与阴道细菌群落同步，并纵向捕捉母亲的反应 到这些社区。我们采用了高效的研究设计，一项成熟的研究 基础设施和著名的基因组测序专业知识来测试生理上看似合理的 未调查的范例，即细菌和病毒群落与母体宿主协调一致 反应可以预测肺结核。

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.