Contribution of immune modulation, metabolism, and microbiota to Group B Streptococcal urinary tract infection

项目总结 尿路感染(UTI)是一种主要的医疗负担，超过一半的女性在 一生，每年在美国产生超过20亿美元的医疗成本。UTI通常是 在健康的成年人中被认为是一种轻微的疾病，很容易通过口服抗生素治愈。但是，具有 异常的抗微生物防御或代谢功能障碍，如2型糖尿病，发生的可能性是前者的两倍。 尿路感染，常发展为并发症，包括复发性尿路感染、肾盂肾炎和尿毒症。某些病原体， 例如B组链球菌(GBS)在糖尿病中出现了奇怪的过度表达，并可能突出独特的 这些患者的宿主尿液防御系统存在缺陷。这项拟议的研究的目标是确定 糖尿病泌尿生殖道功能障碍的分子通路导致易感性增加，增加 毒力和/或增加GBS的定殖率。我们已发表的和初步的研究表明尿液不足 抗菌防御因子和扩增的GBS对糖尿病小鼠的UTI易感性，增强GBS在 糖尿病小鼠的血糖水平和GBS阴道定植增加。这些数据支持 基本尿液防御功能异常、细菌毒力增强和/或 不同的阴道微生物区系增加了2型糖尿病患者对GBS泌尿生殖系统感染的易感性。这 假说将通过以下具体目的进行审问：1)审问塔姆-霍斯费尔的角色 糖蛋白(THP)在GBS UTI中的上皮防御和免疫调节作用，2)评估尿液的影响 血糖水平对GBS膀胱定植和尿路免疫反应的影响，以及3)确定 寄主代谢和阴道微生物区系对GBS定植的影响。这些目标是通过使用多个 创新工具包括纵向多糖分析、高通量阴道微生物培养 社区，生物发光细菌成像，转基因小鼠系，最近建立了人源化 GBS阴道定植的微生物群模型，以及现代微生物群和代谢组谱。这 研究是在贝勒医学院动态和跨学科的环境中进行的， 在GBS-宿主相互作用、微生物群的特征和培养以及类型的临床管理方面的专业知识 2糖尿病。这一研究策略旨在更全面地了解宿主递减的复杂过程 在代谢性疾病期间的防御，以提供新的治疗靶点，可以治疗或预防两种健康人的尿路感染 个人和2型糖尿病患者。

PROJECT SUMMARY Urinary tract infection (UTI) is a major medical burden, afflicting more than half of women at least once in their lifetime, and generating more than $2 billion of healthcare costs annually in the United States. UTI is typically considered a mild medical condition in healthy adults and is readily cured by oral antibiotics. However, hosts with aberrant antimicrobial defenses or metabolic dysfunction, such as type 2 diabetes, are twice as likely to develop UTI and often develop complications including recurrent UTI, pyelonephritis, and urosepsis. Certain pathogens, such as Group B Streptococcus (GBS) are curiously over-represented in diabetes, and may highlight unique deficiencies in host urinary defenses in these patients. The goal of this proposed research is to identify the dysfunctional molecular pathways of the diabetic urogenital tract conferring heightened susceptibility, increased virulence, and/or increased colonization by GBS. Our published and preliminary studies show deficient urinary antimicrobial defense factors and amplified GBS UTI susceptibility in diabetic mice, enhanced GBS fitness in diabetic levels of glucose, and increased GBS vaginal colonization in diabetic mice. These data support the central hypothesis that aberrant function of essential urinary defenses, augmented bacterial virulence, and/or disparate vaginal microbiota enhance susceptibility to GBS urogenital infection in type 2 diabetes. This hypothesis will be interrogated through the following specific aims: 1) Interrogate the role of Tamm-Horsfall glycoprotein (THP) in epithelial defense and immune modulation during GBS UTI, 2) Assess impact of urinary glucose levels on GBS bladder colonization and urinary tract immune responses, and 3) Define the impact of host metabolism and the vaginal microbiota on GBS colonization. These aims are advanced using multiple innovative tools including longitudinal glycan analyses, high-throughput cultivation of vaginal microbial communities, bioluminescent bacterial imaging, transgenic mouse lines, recently established humanized microbiota models of GBS vaginal colonization, and modern microbiome and metabolome profiling. This research takes place in the dynamic and interdisciplinary environment of Baylor College of Medicine with diverse expertise in GBS-host interactions, microbiome characterization and cultivation, and clinical management of type 2 diabetes. This research strategy seeks to more fully understand the complex processes diminishing host defenses during metabolic disease to inform new therapeutic targets that can treat or prevent UTI in both healthy individuals and those with type 2 diabetes.