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

免疫调节、代谢和微生物群对 B 族链球菌尿路感染的影响

基本信息

批准号：
10670976
负责人：
Katy Patras
金额：
$ 47.74万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670976
关键词：
Address Adherence Adult Antibiotics Automobile Driving Binding Biological Biological Models Bladder Cells Cessation of life Clinical Clinical Management Complex Curiosities Data Defect Diabetes Mellitus Diabetic mouse Disparate Economic Burden Elderly Environment Epithelium Genitourinary System Infection Genitourinary system Gestational Diabetes Glucose Glycoproteins Goals Health Care Costs Hospitalization Host Defense Image Immune Immune response Impairment In Vitro Individual Infection Knowledge Leukocytes Mediating Medical Medical Economics Medicine Metabolic Diseases Metabolic dysfunction Metabolism Modeling Modernization Modification Molecular Morbidity - disease rate Mus Nature Non-Insulin-Dependent Diabetes Mellitus Oral Pathway interactions Patients Polysaccharides Population Predisposition Process Proteins Publishing Pyelonephritis Recurrence Research Role Sialic Acids Site Specimen Streptococcus Group B Structure Testing Therapeutic Transgenic Mice United States Urinary tract Urinary tract infection Uropathogen Vagina Virulence Woman antimicrobial blood glucose regulation collaborative environment college diabetic fitness immune function immunoregulation in vivo in vivo Model infection management infection risk innovation insight metabolic profile metabolome microbial microbial community microbiome microbiota mouse model new therapeutic target opportunistic pathogen pathogen permissiveness prevent recruit response tool urinary urogenital tract vaginal microbiota

项目摘要

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.

项目概要尿路感染 (UTI) 是一项重大医疗负担，超过一半的女性在生育期间至少遭受过一次尿路感染 (UTI) 的困扰在美国，每年产生超过 20 亿美元的医疗费用。尿路感染通常是对于健康成年人来说，这种疾病被认为是一种轻微的疾病，并且很容易通过口服抗生素治愈。然而，主机与异常的抗菌防御或代谢功能障碍（例如 2 型糖尿病）发生的可能性是正常人的两倍尿路感染并经常出现并发症，包括复发性尿路感染、肾盂肾炎和尿脓毒症。某些病原体，奇怪的是，B 族链球菌 (GBS) 在糖尿病中所占比例过高，可能会凸显其独特的特征这些患者的宿主泌尿防御缺陷。这项拟议研究的目标是确定糖尿病泌尿生殖道功能失调的分子途径导致易感性增加，毒性和/或 GBS 定植增加。我们已发表的初步研究表明，尿液不足糖尿病小鼠的抗菌防御因子和 GBS UTI 易感性增强，增强了 GBS 的适应性糖尿病小鼠的葡萄糖水平，以及 GBS 阴道定植增加。这些数据支持中心假设是基本泌尿防御功能异常、细菌毒力增强和/或不同的阴道微生物群增加了 2 型糖尿病患者对 GBS 泌尿生殖道感染的易感性。这假设将通过以下具体目标进行质疑： 1) 质疑 Tamm-Horsfall 的作用 GBS UTI 期间糖蛋白 (THP) 在上皮防御和免疫调节中的作用，2) 评估尿的影响葡萄糖水平对 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。这些目标是通过多种手段来推进的创新工具，包括纵向聚糖分析、阴道微生物高通量培养群落、生物发光细菌成像、转基因小鼠系、最近建立的人源化 GBS 阴道定植的微生物群模型，以及现代微生物组和代谢组分析。这研究在贝勒医学院充满活力的跨学科环境中进行， GBS-宿主相互作用、微生物组表征和培养以及类型临床管理方面的专业知识 2 糖尿病。该研究策略旨在更全面地了解减少宿主的复杂过程代谢性疾病期间的防御，为可以治疗或预防健康和健康人群尿路感染的新治疗靶点提供信息个人和 2 型糖尿病患者。