Understanding the pathophysiology of GBS UTI in diabetes

了解糖尿病 GBS UTI 的病理生理学

基本信息

批准号：
10495253
负责人：
Ritwij Kulkarni
金额：
$ 17.17万
依托单位：
UNIVERSITY OF LOUISIANA AT LAFAYETTE
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：
2021-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495253
关键词：
Address Adherence Adhesions Adult Bacteremia Bacteria Bacterial Adhesins Bacteriuria Biological Assay Bladder Cells Characteristics Cytolysins Data Diabetes Mellitus Diabetic Neuropathies Diabetic mouse Disease Epithelial Exhibits Exploratory/Developmental Grant Exposure to Functional disorder Future Gene Expression Genes Genetic Models Genetic Transcription Gestational Diabetes Glucose Glycosuria Goals Hemolysin Hemolysis Histology Histopathology Human Hyperglycemia Immune Immune response Immunosuppression In Vitro Incidence Individual Infection Infiltration Insulin-Dependent Diabetes Mellitus Integration Host Factors Kidney Knowledge Life Metabolic Monitor Non-Insulin-Dependent Diabetes Mellitus Organ Outcome Pathogenesis Physiological Physiology Polysaccharides Predisposition Pregnant Women Production Publications Publishing Pyelonephritis Regulator Genes Research Resistance Risk Sepsis Shapes Sialic Acids Site Skin Spleen Streptococcus Group B Streptozocin Surface Time Tissues Toxin Type 2 diabetic Urinary Retention Urinary tract Urinary tract infection Urine Uropathogen Virulence Virulence Factors antimicrobial peptide LL-37 ascending urinary tract infection capsule comorbidity cytokine cytotoxicity db/db mouse diabetic experimental study fitness gastrointestinal gene network glycemic control immunopathology mouse model mutant nephrotoxicity neutrophil non-diabetic novel pathogen pleiotropism reproductive side effect small molecular inhibitor therapeutically effective transcriptome transcriptome sequencing type I diabetic urinary vaginal microbiota

项目摘要

ABSTRACT Diabetic individuals are more susceptible to urinary tract infections (UTI). Specifically, the risk of UTI caused by Gram positive Streptococcus agalactiae (Group B Streptococcus, GBS) is significantly increased in diabetic individuals. In addition, diabetes also facilitates the progression of GBS-UTI to severe and potentially deadly outcomes such as pyelonephritis, bacteremia, and sepsis. We hypothesize that “the diabetic urinary microenvironment facilitates infection of the urinary tract 1) by augmenting virulence of uropathogenic bacteria and 2) by suppressing host immune defenses.” To address this hypothesis, we have proposed targeted exploratory studies, in alignment with the scope of R21 mechanism, to elucidate GBS factors and host urinary immune defenses central to GBS-UTI pathogenesis in two mechanistically distinct murine models of hyperglycemia: 1) STZ-induced type 1 diabetes and 2) db/db, a genetic model of type 2 diabetes. Previous research has characterized myriad GBS virulence factors such as surface adhesins, pore forming toxins, and gene regulators facilitating GBS survival and virulence in the urinary tract. Studies using mouse model of ascending UTI have also revealed distinctive urinary immune responses induced by GBS-UTI. However, two important knowledge gaps exist in our understanding of GBS-UTI pathogenesis in diabetes: 1) the pleiotropic effects of host diabetic urinary microenvironment on GBS physiology are undefined and 2) specific host mechanisms responsible for increased urinary GBS burden observed in diabetic mice are not fully deciphered. To fill these knowledge gaps we propose: Specific Aim 1 Identify and characterize specific GBS factors important for uropathogenesis in diabetic mice. We will compare RNA-sequencing profiles of GBS isolated from diabetic and non-diabetic urinary tracts to identify differentially transcribed virulence, regulatory and metabolic gene expression networks. The experiments proposed in SA1 are founded on our published results that in vitro exposure to moderate glycosuria significantly increases GBS virulence. Specific Aim 2 Evaluate pathophysiology of GBS-UTI in type 1 and type 2 diabetic mice. In this aim we will induce ascending UTI by inoculating GBS into STZ-type 1 and db/db type 2 diabetic mice and their non- diabetic littermates and examine differences in disease parameters such as bacterial burden, cytokine production, immune cell infiltration and histopathology of the urinary tract. The experiments in SA2 are founded on supporting data that at 24h after intravesicular inoculation with GBS, db/db diabetic mice exhibit significantly higher bacterial burden in bladder and kidneys and increased dissemination to spleen. In addition to heralding significant advances in the field of GBS-UTI, our results will pave the way for research into the effects of diabetes on the pathogenesis of other uropathogens, identifying novel host/pathogen targets against which small molecular inhibitors may ultimately be developed as effective therapeutics to treat UTI.

抽象的糖尿病患者更容易受到尿路感染（UTI）。具体而言，由糖尿病患者的革兰氏阳性链球菌（B组链球菌，GBS）显着增加此外，糖尿病还促进了GBS-UTI到严重且可能致命的进展肾上腺炎，细菌和败血症等结果。我们假设“糖尿病尿微环境促进尿路的感染1）通过增强尿道病病毒细菌和2）通过抑制宿主的免疫防御。”为了解决这一假设，我们提出了针对R21机制范围的针对探索性研究，以阐明GBS因子和宿主在两个机械上不同的鼠模型的GBS-UTI发病机理的中心防御高血糖：1）STZ诱导的1型糖尿病和2）DB/DB，这是2型糖尿病的遗传模型。先前的研究表征了无数GBS病毒因子，例如表面粘合剂，孔形成毒素和基因调节剂支持尿路中的GBS存活和病毒。使用鼠标的研究上升UTI的模型还揭示了GBS-UTI引起的独特尿免疫反应。但是，在我们对糖尿病中GBS-UTI发病机理的理解中，存在两个重要的知识差距： 1）宿主糖尿病尿液微环境对GBS生理学的多效性影响不确定，并且 2）在糖尿病小鼠中观察到的泌尿GB燃烧增加的特定宿主机制不是为了填补这些知识空白，我们提出了：特定目标1识别并表征特定的GBS因子对糖尿病中尿路病重要的重要老鼠。我们将比较从糖尿病和非糖尿病尿道中分离出的GB的RNA测序曲线识别不同转录的病毒，调节性和代谢基因表达网络。 SA1中提出的实验建立在我们发布的结果上，该结果体外暴露于现代糖尿症显着增加了GBS病毒。特定目标2评估1型和2型糖尿病小鼠中GBS-UTI的病理生理学。在这个目标中我们将通过将GBS接种到STZ型1和DB/DB 2型糖尿病小鼠及其非 - 糖尿病窝窝和检查疾病参数的差异，例如细菌燃烧，细胞因子尿路的产生，免疫细胞浸润和组织病理学。 SA2中的实验是建立的关于支持GBS经内接种后24H的数据，DB/DB糖尿病小鼠显着暴露膀胱和肾脏中较高的细菌燃烧，并增加对索伦的传播。除了预示GBS-UTI领域的重大进展外，我们的结果还将为研究铺平道路进入糖尿病对其他尿道病的发病机理的影响，鉴定出新的宿主/病原体靶标最终可以将小分子抑制剂作为治疗UTI的有效疗法开发。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systematic Review of Literature Examining Bacterial Urinary Tract Infections in Diabetes.

DOI：
10.1155/2022/3588297
发表时间：
2022
期刊：
JOURNAL OF DIABETES RESEARCH
影响因子：
4.3
作者：
Paudel, Santosh;John, Preeti P.;Poorbaghi, Seyedeh Leila;Randis, Tara M.;Kulkarni, Ritwij
通讯作者：
Kulkarni, Ritwij

Glycosuria Alters Uropathogenic Escherichia coli Global Gene Expression and Virulence.