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

项目摘要 尿路感染（UTI）是一个主要的医疗负担，超过一半的妇女在其一生中至少有一次受到影响。 终身，并在美国每年产生超过20亿美元的医疗费用。UTI通常 被认为是健康成年人的一种轻度疾病，很容易通过口服抗生素治愈。但是， 异常的抗菌防御或代谢功能障碍，如2型糖尿病， 泌尿道感染，并经常发展的并发症，包括复发性泌尿道感染，肾盂肾炎，尿脓毒症。某些病原体， 例如B族链球菌（GBS）在糖尿病中奇怪地过度出现， 这些患者的宿主泌尿系统防御能力不足。这项研究的目的是确定 糖尿病泌尿生殖道的分子途径功能障碍，使易感性增加， 毒力和/或GBS定植增加。我们发表的和初步的研究表明，缺乏尿 抗微生物防御因子和放大的GBS UTI易感性，增强GBS适应性， 糖尿病小鼠中的葡萄糖水平和增加的GBS阴道定植。这些数据支持 核心假设是基本的泌尿系统防御功能异常，细菌毒力增强，和/或 不同阴道微生物群增加2型糖尿病患者GBS泌尿生殖道感染的易感性这 我们将通过以下具体目标来探讨这一假设：1）探讨Tamm-Horsfall的作用 GBS UTI期间上皮防御和免疫调节中的糖蛋白（THP），2）评估尿 葡萄糖水平对GBS膀胱定植和尿路免疫反应的影响，以及3）定义 宿主代谢和阴道微生物群对GBS定植的影响。这些目标是先进的使用多个 创新的工具，包括纵向聚糖分析，高通量培养阴道微生物 社区，生物发光细菌成像，转基因小鼠品系，最近建立的人源化 GBS阴道定殖的微生物群模型以及现代微生物组和代谢组分析。这 研究发生在贝勒医学院的动态和跨学科的环境中， 在GBS-宿主相互作用，微生物组表征和培养以及临床管理类型 2糖尿病.这项研究策略旨在更全面地了解减少宿主的复杂过程， 代谢疾病期间的防御，以告知新的治疗目标，可以治疗或预防UTI在两个健康 2型糖尿病患者的饮食习惯

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.