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: 10657698
• 负责人: HARRY L. MOBLEY
• 金额: $ 74.99万
• 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/10657698
• 关键词: 21 year old; Age; Animal Model; Applied Research; Bacteria; Bacterial Genes; Basic Science; Behavior; Bladder; Cessation of life; Classification; 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; Intestines; Life Style; Measures; Mission; Modeling; Molecular; Monitor; Mus; National Institute of Allergy and Infectious Disease; Older Population; Outcome; Pathogenesis; Patients; Pattern; Population; Postmenopause; Predisposition; 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; virulence gene; 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.

了解尿路感染的发病机理（UTI）由尿道疾病大肠杆菌引起 （UPEC），两者都跟进我们对UPEC制定的转录程序的确定至关重要 在年轻女性中简单的UTI期间，了解宿主病原体的相似性和差异 年轻与绝经后患者的相互作用。这允许对年轻女性的先前研究的见解 直接应用于老年人。我们将建模从初始定植到开发的感染 膀胱中的急性感染，以鉴定诱导UPEC快速生长的机制。另外，没有 定义了感染绝经后妇女的UPEC菌株转录程序的研究，这是一个关键的高 冲击队列通常患有复发性UTI（RUTI）。实际上，尿路斯有责任15.5％ 65岁以上的女性住院和6.2％的死亡。比较UPEC基因的模式至关重要 这两组患者的表达差异很大。我们的 长期研究目标是了解UPEC如何在人类尿路中殖民，避免免疫 响应并损坏主机。在此资助期间的目的是跟进我们的转录组 在简单的UTI中进行的研究，了解如何随着时间的推移部署基因表达并评估UPEC 绝经后妇女的转录组监测细菌因素对感染发展重要的细菌因素，我们 中心假设是尿路感染的终点是顺序宿主病原的结果 互动，其中UPEC颁布了一项高度保守的监管程序，以应对其与 主持人。拟议工作的理由是，一旦我们确定了UPEC的转录程序 殖民的早期阶段，我们可以专注于针对这些特定的干预和预防 目标。我们将通过实现两个具体目标来检验我们的中心假设，并完成目标： 1）确定UPEC在尿路中的时间基因表达程序从开始到 使用升上UTI的小鼠模型来开发膀胱的急性感染并阐明 诱导UPEC在尿路中快速生长的分子机制。 2）确定绝经后妇女UTI期间UPEC期间的转录组和增长率。 预期的结果将是对UTI期间全球UPEC基因表达的时间评估，并且 绝经后妇女的UPEC基因表达。随着时间的流逝，所有UPEC基因的表达将被遵循 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。触发快速的代谢产物 患者和小鼠将确定增长率。这些研究的积极影响将是铺平道路 通过了解尿路中的基因表达的进展，以预防疾病，并确定 强调UTI感染的代谢产物。了解表达的特定毒力因子和核心基因 UPEC将允许开发针对新目标的特定治疗剂。