Understanding the pathophysiology of GBS UTI in diabetes

了解糖尿病 GBS UTI 的病理生理学

• 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
• 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

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.

摘要

项目成果

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

对糖尿病中细菌尿路感染的文献进行系统评价。

• 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.

• DOI: 10.1128/msphere.00004-22
• 发表时间: 2022-06-29
• 期刊: mSphere
• 影响因子: 4.8

A Systematic Review of the Literature Examining the Effects of Cigarette Smoke and e-Cigarette Vapor on the Virulence of Human Pathogenic Bacteria.

• DOI: 10.3390/ijerph191912518
• 发表时间: 2022-09-30
• 期刊: INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
• 作者: Bagale, Kamal;Kulkarni, Ritwij
• 通讯作者: Kulkarni, Ritwij