E. coli virulence gene expression during clinical UTIs in women

女性临床尿路感染期间大肠杆菌毒力基因的表达

• 批准号: 10515444
• 负责人: HARRY L. MOBLEY
• 金额: $ 77.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515444
• 关键词: 21 year old; Animal Model; Applied Research; Bacteria; Bacterial Genes; Basic Science; Behavior; Bladder; Cessation of life; Clinical; Communicable Diseases; Development; Disease; Elderly woman; Environment; Escherichia coli; Funding; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Growth; Hospitalization; Human; Immune response; Infection; Infective cystitis; Intervention; Life Style; Measures; Mission; Modeling; Molecular; Monitor; Mus; National Institute of Allergy and Infectious Disease; Older Population; Outcome; Pathogenesis; Patients; Pattern; Population; Postmenopause; Prevention; Proxy; Public Health; Recurrence; Research; Testing; Therapeutic; Time; United States National Institutes of Health; Urinary tract; Urinary tract infection; Urine; Uropathogenic E. coli; Virulence; Virulence Factors; Woman; Work; acute infection; ascending urinary tract infection; cohort; cost; disorder prevention; fitness; follow-up; human old age (65+); insight; mouse model; novel; pathogen; pathogenic Escherichia coli; prevent; programs; rapid growth; response; time use; transcriptome; young woman

To understand the pathogenesis of urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC), it is critical to both follow up on our determination of the transcriptional program enacted by UPEC during uncomplicated UTI in young women and to understand similarities and differences in host-pathogen interactions in young versus postmenopausal patients. This allows insights from prior studies in young women to be directly applied to the older population. We will model infection from initial colonization to development of acute infection in the bladder to identify mechanisms that induce rapid growth of UPEC. In addition, there are no studies defining the transcriptional program of UPEC strains that infect postmenopausal women, a critical high impact cohort that commonly suffers from recurrent UTI (rUTI). Indeed, UTIs are responsible for 15.5% of hospitalizations and 6.2% of deaths in women over 65 years old. It is vital to compare patterns of UPEC gene expression between these two groups of patients who present with dramatically different bladder milieus. Our long-term research goal is to understand how UPEC colonizes the human urinary tract, eludes the immune response, and damages the host. The objective during this funding period is to follow up on our transcriptome studies in uncomplicated UTIs, understanding how gene expression is deployed over time and assess the UPEC transcriptome in postmenopausal women to monitor bacterial factors important for development of infection, Our central hypothesis is that the end point of urinary tract infection is a consequence of sequential host-pathogen interactions, wherein UPEC enacts a highly conserved regulatory program in response to its encounter with the host. The rationale for the proposed work is that once we identify the transcriptional program of UPEC during early stages of colonization, we can focus efforts on intervention and prevention directed toward these specific targets. We will test our central hypothesis and complete our objectives by carrying out two specific aims: 1) Determine the temporal gene expression program of UPEC in the urinary tract from initiation to development of acute infection of the bladder using the mouse model of ascending UTI and elucidate the molecular mechanism that induces rapid growth of UPEC in the urinary tract. 2) Determine the transcriptomes and growth rates of UPEC during UTI in postmenopausal women. Expected outcomes will be a temporal assessment of global UPEC gene expression during UTI and a measure of UPEC gene expression in postmenopausal women. Expression of all UPEC genes will be followed over time using UPEC strains isolated from young patients in the validated mouse UTI model. Metabolites that trigger rapid growth rates will be identified in patients and mice. The positive impact of these studies will be to pave the way to disease prevention by understanding the progression of gene expression over time during UTI and identifying metabolites that accentuate infection in UTI. Understanding specific virulence factors and core genes expressed by UPEC will allow development of specific therapeutics against novel targets.

了解尿路致病性大肠杆菌引起的尿路感染 (UTI) 的发病机制 (UPEC)，跟进我们对 UPEC 制定的转录程序的确定至关重要 在年轻女性的无并发症尿路感染期间进行研究，并了解宿主病原体的相似性和差异 年轻患者与绝经后患者的相互作用。这可以从之前针对年轻女性的研究中获得见解 直接应用于老年人口。我们将模拟从最初的定植到发展的感染过程 膀胱急性感染，以确定诱导 UPEC 快速生长的机制。此外，没有 研究定义了感染绝经后妇女的 UPEC 菌株的转录程序，这是一个临界高值 通常患有复发性尿路感染 (rUTI) 的影响人群。事实上，15.5% 的尿路感染是由尿路感染造成的。 65 岁以上女性住院治疗和死亡的比例为 6.2%。比较 UPEC 基因模式至关重要 这两组患者之间的表达存在显着不同的膀胱环境。我们的 长期研究目标是了解 UPEC 如何在人类尿道中定殖，逃避免疫系统的攻击 响应，并损坏主机。本资助期间的目标是跟进我们的转录组 研究简单的尿路感染，了解基因表达如何随着时间的推移而部署并评估 UPEC 绝经后妇女的转录组监测对感染发展重要的细菌因素，我们的 中心假设是尿路感染的终点是宿主-病原体连续作用的结果 相互作用，其中 UPEC 制定了高度保守的监管计划以应对与 主持人。这项工作的基本原理是，一旦我们确定了 UPEC 的转录程序， 在殖民化的早期阶段，我们可以集中精力针对这些具体的干预和预防 目标。我们将测试我们的中心假设并通过实现两个具体目标来完成我们的目标： 1) 确定泌尿道中UPEC从起始到表达的时间基因表达程序 使用上行性尿路感染小鼠模型进行膀胱急性感染的发展并阐明 诱导尿道中 UPEC 快速生长的分子机制。 2) 确定绝经后妇女尿路感染期间 UPEC 的转录组和生长率。 预期结果是对 UTI 期间全球 UPEC 基因表达进行时间评估并采取措施 绝经后妇女 UPEC 基因表达的影响。所有 UPEC 基因的表达将随着时间的推移进行跟踪 在经过验证的小鼠 UTI 模型中使用从年轻患者中分离出的 UPEC 菌株。快速触发的代谢物 将确定患者和小鼠的生长率。这些研究的积极影响将为 通过了解尿路感染期间基因表达随时间的进展并识别 加重尿路感染感染的代谢物。了解特定毒力因子和表达的核心基因 UPEC 将允许开发针对新靶点的特异性疗法。