E. coli virulence gene expression during clinical UTIs in women

泌尿系致病性大肠埃希菌尿路感染发病机制的研究 (UPEC)，对我们确定UPEC颁布的转录计划的后续行动至关重要 青年女性非复杂性尿路感染及宿主病原学的异同 年轻患者与绝经后患者的相互作用。这使得对年轻女性的先前研究有了深入的了解。 直接适用于老年人口。我们将模拟从最初的殖民到发展的感染 膀胱的急性感染，以确定导致UPEC快速生长的机制。此外，还没有 研究确定感染绝经后妇女的UPEC菌株的转录程序，这是一个临界的高水平 通常患有复发性尿路感染(RUTI)的影响队列。事实上，城市交通运输机构负责15.5%的 65岁以上妇女住院和死亡的比例为6.2%。UPEC基因模式的比较至关重要 这两组患者的膀胱环境明显不同。我们的 长期的研究目标是了解UPEC如何定植于人的尿路，逃避免疫 响应，并损坏主机。在此资助期间的目标是跟进我们的转录组 研究不复杂的尿路感染，了解基因表达是如何随着时间的推移而部署的，并评估UPEC 绝经后妇女转录组监测感染发生的重要细菌因素，我们的 中心假说是尿路感染的终点是连续宿主病原体的结果。 互动，其中UPEC制定了一个高度保守的监管计划，以回应它遇到的 主持人。拟议工作的基本原理是，一旦我们确定了UPEC在 在殖民的早期阶段，我们可以集中力量针对这些特定的 目标。我们将检验我们的中心假设，并通过实现两个具体目标来完成我们的目标： 1)确定UPEC在尿路中的时间基因表达程序 上行性尿路感染小鼠急性膀胱炎模型的建立及意义 尿路上皮细胞快速生长的分子机制。 2)测定绝经后妇女尿路感染过程中UPEC的转录和生长速度。 预期结果将是在UTI期间对全球UPEC基因表达的时间评估和测量 绝经后妇女UPEC基因表达的变化。所有UPEC基因的表达将随着时间的推移而变化 在验证的小鼠尿路感染模型中使用从年轻患者中分离的UPEC菌株。引发快速反应的代谢物 将确定患者和小鼠的增长率。这些研究的积极影响将是为 通过了解尿路感染期间基因表达随时间的进展并识别 会加重尿路感染的代谢物。了解特定的毒力因子和表达的核心基因 通过UPEC，将能够针对新的靶点开发特定的疗法。

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.