Characterizing the impact of maternal immune response to urinary tract infection on preterm birth

早产是一岁以下婴儿死亡的主要原因，导致100多万新生儿死亡。 每年的死亡人数。存活的早产儿感染风险增加，神经发育障碍， 以及心血管和肺部疾病。母体宫外感染，如尿路感染 (UTI)与早产风险增加有关；然而，UTI中的宿主-微生物动态- 相关的早产并没有得到很好的描述。为了研究这一现象，我们开发了一种小鼠模型 与尿路感染相关的早产与尿路致病性大肠杆菌(UPEC)，超过70%的尿路感染的病原体。 在我们的模型中，大约一半的水坝早产，而其余的水坝没有分娩。 在实验终点之前。这种双峰表型使我们能够独一无二地研究因素 导致早产的发生。早产儿的膀胱和胎盘细菌减少 负担和更多的胎儿死亡。此外，当水坝被紫外线感染时，早产得以维持。 灭活细菌，这表明早产是由于炎症而不是细菌传播。 此外，早产小鼠的胎盘表达升高的MIP2，一种鼠中性粒细胞趋化因子，提示 中性粒细胞在早产发病机制中的作用这让我们产生了与尿路感染相关的早产的假设 归因于局限性的膀胱炎和独特的全身和生殖免疫特征 在早产期水坝与长期水坝相比。这一假设将通过两个目标进行调查：一个是 比较了早产儿和足月儿的局部膀胱免疫反应，并阐明了差异 与尿路感染相关的足月和早产孕妇的母体系统和生殖免疫特征。目标1 靶向耗竭足月和早产小鼠膀胱中夫妇无偏多重免疫图谱的研究 内毒素和中性粒细胞，这两种成分与早产和不良新生儿结局有关。目标2 旨在了解尿路感染的母体免疫学后果以及它们可能如何与 通过研究母体、子宫和胎盘免疫细胞的组成和功能来研究早产。 我们将利用我们的新的小鼠模型来研究早产发生率和不良反应的表型变化。 通过多参数流式细胞术和细胞因子分析将胎儿结局与分子机制相结合。 这些实验不仅将是第一次探索导致尿路感染相关早产的机制 出生，但他们也将是第一个全面描述膀胱对感染的免疫反应的人 在怀孕期间。这项工作的成功将揭示新的治疗机会，以预测、减少或 防止早产。这项建议将允许申请人进一步发展她的技术技能和知识。 免疫学教授，同时将她的专业知识扩展到包括小鼠感染和怀孕模型以及 生殖生物学。最终，这项工作将使申请者获得晋升所需的经验 致力于学术研究，同时解决孕产妇和胎儿健康结果方面的重大差距。

Preterm birth is the leading cause of mortality in infants under age one, resulting in over one million neonatal deaths annually. Surviving preterm infants experience increased risk of infection, neurodevelopmental disorders, and cardiovascular and pulmonary disease. Maternal extra-uterine infections, such as urinary tract infection (UTI), are associated with increased risk for preterm birth; however, the host-microbe dynamics in UTI- associated preterm birth are not well-described. To study this phenomenon, we have developed a murine model of UTI-associated preterm birth with uropathogenic E. coli (UPEC), the causative agent of over 70% of UTIs. In our model, approximately half of dams went into preterm labor while remaining dams did not go into labor before the experimental end point. This bimodal phenotype enables us to uniquely investigate factors contributing to preterm birth incidence. Preterm dams exhibited decreased bladder and placental bacterial burdens and increased fetal demise. Further, preterm birth was maintained when dams were infected with UV- inactivated bacteria, suggesting preterm birth is attributed to inflammation rather than bacterial dissemination. Additionally, placentae from preterm mice expressed elevated MIP2, a murine neutrophil chemokine, implicating neutrophils in preterm birth pathogenesis. This led us to the hypothesis that UTI-associated preterm birth is attributed to localized bladder inflammation and distinct systemic and reproductive immune profiles in preterm dams compared to term dams. This hypothesis will be investigated through two aims: one which compares localized bladder immune response in preterm and term dams, and one which elucidates divergences in maternal systemic and reproductive immune profiles in UTI-associated term and preterm pregnancy. Aim 1 couples unbiased, multiplexed immune profiling in the bladder of term and preterm mice with targeted depletion of LPS and neutrophils, two components implicated in preterm birth and adverse neonatal outcomes. Aim 2 seeks to understand the maternal immunological consequences of UTI and how they may be associated with preterm birth by investigating maternal systemic, uterine, and placental immune cell composition and function. We will utilize our novel murine model to investigate phenotypic changes in preterm birth incidence and adverse fetal outcomes coupled with molecular mechanism through multiparameter flow cytometry and cytokine analysis. These experiments will not only be the first to explore mechanisms that contribute to UTI-associated preterm birth, but they will also be the first to comprehensively characterize the bladder immune response to infection during pregnancy. The success of this work will reveal novel therapeutic opportunities to predict, reduce, or prevent preterm birth. This proposal will allow the applicant to further develop her technical skills and knowledge of immunology, while expanding her expertise to include murine models of infection and pregnancy and reproductive biology. Ultimately, this work will equip the applicant with the experience necessary to advance her career in academic research while addressing a critical gap in maternal and fetal health outcomes.