The role of host-microbial interactions in altering preterm birth risk among black women

在美国，每年有40万婴儿早产，导致婴儿死亡率比世界上其他26个经济发达国家还要高。早产（PTB）的风险在美国社会中分布不均，导致黑人妇女的风险比白色妇女高50%。人们普遍认为，遗传变异不能解释PTB风险的种族差异，因此其他生物学因素必须对PTB的差异起一定的作用。人类微生物组项目（HMP）的大量工作为女性生殖健康提供了关键信息，特别是描述了占据宫颈阴道（CV）空间的微生物群落的组成。在非妊娠女性中进行的全面研究已将CV微生物群落分类为群落状态类型（CST）。随后的研究表明，选择性CST与各种病理学有关，如性传播疾病， 感染、细菌性阴道病和尿路感染。然而，关于这些CST与自发性PTB（sPTB）相关性的数据受到现有研究的限制，这些研究受到样本量小、缺乏种族多样性和表型不一致的混淆。在为母公司RO 1提供资金的情况下，我们最近公布了2000名种族和民族多样化的女性队列的结果。这项研究提供了结论性的数据，CST和特定的细菌类群与sPTB密切相关。此外，我们发现局部CV免疫应答改变了与高风险CST相关的sPTB风险，表明CV微生物免疫特征对sPTB风险至关重要。我们的数据提供了对已知的sPTB种族差异的可能见解，表明黑人女性更有可能被高风险的CST定殖，并且具有改变sPTB风险的CV免疫介质的差异表达。虽然我们的研究结果表明有机会进行治疗干预以减少sPTB，但最近的进展表明，只有通过了解整个生态系统和随后的宿主反应，我们才能对健康和疾病产生最大的影响。在这项提案中，我们处于独特的地位，通过破译CV微生物群在大量表型良好的sPTB中的作用，以严格推进这一领域。我们还准备通过集中对黑人妇女进行更多的研究来解决不平等问题。这些研究将揭示sPTB的创新生物学机制，包括1）选择的CST是否与宫颈过早重塑的分子证据相关，2）妊娠前是否存在高风险CV微生物免疫特征和/或妊娠是否使女性处于有利或不利状态。解决这些知识差距将提供新的信息，以了解潜在的新干预窗口，并确定与高风险CV微生物免疫状态相关的潜在修饰剂，这可能导致黑人女性sPTB的减少。

In the United States, 400,000 infants are born preterm each year resulting in an infant mortality rate that is worse than 26 other economically developed countries in the world. Preterm birth (PTB) risk is not evenly distributed throughout American society, resulting in massive racial disparities with black women having 50% higher risk than white women. It is widely accepted that genetic variation does not explain racial differences in PTB risk, hence other biological factors must have some obligatory role for disparities in PTB. Extensive work from the Human Microbiome Project (HMP) has provided key information for women’s reproductive health, and specifically has characterized the composition of the microbial communities that occupy the cervicovaginal (CV) space. Comprehensive studies in non-pregnant women have led to the classification of CV microbial communities into community state types (CSTs). Subsequent research has demonstrated that select CSTs are associated with various pathologies such as sexually transmitted infections, bacterial vaginosis, and urinary tract infections. Yet, the data on the association of these CSTs with spontaneous PTB (sPTB) has been limited with existing studies confounded by small sample sizes, lack of racial diversity and inconsistent phenotyping. With funding for the parent RO1, we recently published the results of our racially and ethnically diverse 2000 women cohort. This study provides conclusive data that CSTs and specific bacterial taxa are strongly associated with sPTB. Furthermore, we found that local CV immune responses modify the risk of sPTB associated with high-risk CSTs, suggesting that CV microbial-immune profiles are of critical importance for sPTB risk. Providing possible insight into the known racial disparity with sPTB, our data demonstrate that black women are more likely to be colonized with a high-risk CSTs and have differential expression of CV immune mediators that modify the risk of sPTB. While our findings suggest an opportunity for therapeutic interventions to reduce sPTB, recent advances suggest that only by understanding the totality of an ecosystem and the subsequent host response can we have the greatest impact on health and disease. In this proposal, we are uniquely positioned to advance this field with rigor by deciphering the role of the CV microbiota in a large cohort of well-phenotyped sPTB. We are also poised to address disparities by focusing additional studies on black women. These studies will reveal innovative biological mechanisms in sPTB including 1) whether select CSTs are associated with molecular evidence of premature cervical remodeling and 2) whether high-risk CV microbial-immune profiles are present prior to pregnancy and/or does pregnancy shift women to a favorable or unfavorable state. Addressing these gaps in knowledge will provide novel information as to potential new windows for intervention as well as identifying potential modifiers associated with a high-risk CV microbial-immune state which could lead to a reduction of sPTB in black women.