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

在美国，每年有40万名婴儿早产，导致婴儿死亡率低于世界上其他26个经济发达国家。早产(PTB)的风险在整个美国社会并不均匀分布，导致了巨大的种族差异，黑人女性的风险比白人女性高50%。人们普遍认为，遗传变异不能解释肺结核风险的种族差异，因此，其他生物因素肯定对肺结核的差异起到了一定的强制作用。人类微生物组项目(HMP)的广泛工作为妇女的生殖健康提供了关键信息，并具体描述了占据宫颈阴道(CV)空间的微生物群落的组成。对非怀孕妇女的综合研究导致将心血管微生物群落分类为社区状态类型(CST)。后来的研究表明，特定的CST与各种病理因素有关，如性传播 感染、细菌性阴道病和尿路感染。然而，关于这些CST与自发性肺结核(SPTB)的相关性的数据一直有限，现有的研究受到样本量小、缺乏种族多样性和表型不一致的困扰。在为父母RO1提供资金的情况下，我们最近公布了我们的种族和民族多样化的2000名女性队列的结果。这项研究提供了确凿的数据，即CST和特定的细菌分类群与sPTB密切相关。此外，我们发现局部CV免疫反应改变了与高危CST相关的sPTB的风险，这表明CV微生物免疫特征对于sPTB风险至关重要。我们的数据显示，黑人女性更有可能被高危CST定植，并具有改变sPTB风险的CV免疫介质的差异表达，这为了解sPTB的已知种族差异提供了可能。虽然我们的发现为治疗干预减少肺结核提供了机会，但最近的进展表明，只有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，通过破译大量表型良好的sPTB中CV微生物区系的作用，以严格推动这一领域的发展。我们还准备通过将更多的研究重点放在黑人女性身上来解决差异。这些研究将揭示sPTB的创新生物学机制，包括1)选定的CST是否与宫颈过早重塑的分子证据有关，2)高危心血管微生物免疫谱在怀孕前是否存在和/或怀孕是否将妇女转变为有利或不利的状态。解决这些知识差距将提供关于潜在干预新窗口的新信息，并确定与高风险心血管微生物免疫状态相关的潜在修饰物，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.