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

表征母体免疫反应对尿路感染对早产的影响

• 批准号: 10605459
• 负责人: Samantha Ottinger
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-09 至 2025-12-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605459
• 关键词: Address; Age; Antibiotics; Automobile Driving; Bacteria; Biological Markers; Bladder; Cardiovascular Diseases; Career Mobility; Cells; Cerebral Palsy; Coupled; Couples; Data; Diagnosis; Escherichia coli; Exhibits; Female; Fetal health; Fetus; Flow Cytometry; Immune; Immune response; Immunologics; Immunology; Incidence; Infant; Infection; Inflammation; Inflammatory; Knowledge; Lipopolysaccharides; Lung diseases; Maternal Health; Meta-Analysis; Microbe; Modality; Modeling; Molecular; Mus; Neurodevelopmental Disorder; Neutrophil Activation; Outcome; Pathogenesis; Pathway interactions; Phenotype; Placenta; Pregnancy; Premature Birth; Premature Infant; Premature Labor; Reproductive Biology; Reproductive Health; Research; Research Personnel; Risk; Systemic infection; Technical Expertise; Testing; Therapeutic; Third Pregnancy Trimester; Time; Urinary tract infection; Uropathogenic E. coli; Uterus; Work; career; chemokine; cytokine; experience; experimental study; fetal; immune activation; improved; infection risk; intrauterine infection; maternal serum; mortality; mouse model; neonatal death; neonatal outcome; neutrophil; novel; novel therapeutics; perinatal outcomes; prevent; reproductive; response; skills; standard of care; success

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.

早产是一岁以下婴儿死亡的主要原因，导致超过一百万名新生儿 每年死亡人数。幸存的早产儿感染、神经发育障碍、 以及心血管和肺部疾病。产妇宫外感染，如尿路感染 （尿路感染），与早产风险增加有关；然而，尿路感染中的宿主-微生物动态 相关的早产尚未得到很好的描述。为了研究这种现象，我们开发了小鼠模型 尿路感染相关早产的尿路致病性大肠杆菌 (UPEC) 是 70% 以上尿路感染的病原体。 在我们的模型中，大约一半的母猪早产，而其余的母猪没有分娩 在实验终点之前。这种双峰表型使我们能够独特地研究因素 导致早产发生率。早产母鼠膀胱和胎盘细菌减少 负担和增加胎儿死亡。此外，当母鼠感染了紫外线时，早产现象仍然存在。 灭活的细菌，表明早产归因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（一种小鼠​​中性粒细胞趋化因子），这表明 中性粒细胞在早产发病机制中的作用。这使我们得出这样的假设：尿路感染相关的早产 归因于局部膀胱炎症以及独特的系统和生殖免疫特征 早产母鼠与足月母鼠相比。这一假设将通过两个目标进行研究：一是 比较早产母鼠和足月母鼠的局部膀胱免疫反应，并阐明差异 尿路感染相关的足月和早产孕妇的全身和生殖免疫特征。目标1 将足月小鼠和早产小鼠膀胱中的无偏性、多重免疫分析与靶向消除结合起来 LPS 和中性粒细胞是与早产和不良新生儿结局有关的两个成分。目标2 试图了解尿路感染对母体免疫的影响以及它们如何与 通过研究母体全身、子宫和胎盘免疫细胞的组成和功能来预防早产。 我们将利用我们的新型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结合起来。 这些实验不仅将首次探索导致尿路感染相关早产的机制 但他们也将是第一个全面表征膀胱对感染的免疫反应的人 怀孕期间。这项工作的成功将揭示新的治疗机会来预测、减少或 预防早产。该提案将使申请人能够进一步发展她的技术技能和知识 免疫学，同时扩大她的专业知识，包括感染和怀孕的小鼠模型和 生殖生物学。最终，这项工作将为申请人提供必要的经验，以促进她的进步 从事学术研究，同时解决孕产妇和胎儿健康结果方面的重大差距。