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

基本信息

批准号：
8707441
负责人：
HARRY L. MOBLEY
金额：
$ 23.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707441
关键词：
Accident and Emergency department Acute Adherence Affect Antigens Bacteria Bacterial Adhesins Bacterial Infections Bacteriuria Bladder Clinic Clinical Collection Cystitis Data Development Disease Escherichia coli Frequencies Funding Gastroenteritis Gene Expression Gene Expression Profile Genes Goals Grouping Hospitalization Human Immune response In Vitro Incidence Infection Intervention Iron Kidney Kidney Diseases Knowledge Lead Life Measurement Measures Mission Modeling Morbidity - disease rate Mus Nature Outcome Pathogenesis Phylogeny Physicians Preventive Intervention Production Proteins Public Health Recurrence Research Respiratory System Respiratory tract structure Scourge Site Source Sum Symptoms System Systems Biology Testing Toxin United States Urinary tract Urinary tract infection Urologic Diseases Urology Uropathogenic E. coli Vaccines Virulence Virulence Factors Virulent Visit Woman Work acute pyelonephritis ascending urinary tract infection base cost experience fitness in vivo inhibitor/antagonist men pathogenic Escherichia coli prevent therapeutic development therapeutic target tool vaccine development

项目摘要

DESCRIPTION (provided by applicant): The urinary tract is among the most common sites of bacterial infection and E. coli is by far the most common species infecting this site. Most data regarding expression of uropathogenic E. coli (UPEC) virulence genes has come from in vitro studies or the murine model of urinary tract infection (UTI). It is not clear how gene expression in the murine model compares to gene expression during a clinical UTI in humans. Lack of such knowledge may prevent research that focuses on the most highly expressed virulence mechanisms and even lead to work not relevant to human infection. Our long term research goal is to understand how UPEC colonize the human urinary tract, avoid the immune response, and damage the host. The objective during this funding period is to determine the levels of expression of the three classes of UPEC genes during clinical UTI in women that most affect virulence: adhesin, iron acquisition system, and toxin genes. Our central hypothesis is that the virulence of a UPEC strain is the sum of its capacity for adherence, iron acquisition, and toxin production. The rationale for the proposed work is that once we identify the most highly expressed virulence genes during UTI in humans, we can focus efforts on intervention directed toward these highly expressed targets. We will achieve our objective by completing the following specific aims: 1) Determine the adhesins expressed during UTI in humans; 2) determine the iron acquisition systems required for cystitis and those required for acute pyelonephritis; and 3) Determine the toxins expressed during human UTI that predict virulence. The expected outcomes of conducting these three aims will be a precise assessment of virulence gene expression by UPEC strains during recurrent and uncomplicated UTI in women. Given a specific virulence gene profile, we will be able to predict the potential for virulence of that particular strain. The positive impact of these studies will be substantial. We will precisely define the nature of a UPEC strain as they differ from commensal strains. We will understand which virulence determinants including adhesins, iron acquisition system proteins, and toxins are expressed during clinical UTI in women and to what degree they are expressed. At the conclusion of our project we will have definitively quantified global gene expression in UPEC strains during acute UTI in women. These findings will be critical to the field because they will identify virulence determinants expressed by UPEC during UTI in women that will clarify the mechanism of pathogenesis, classify therapeutic targets, and highlight antigens with potential for vaccine development.

描述（由申请人提供）：尿路是细菌感染的最常见部位，而大肠杆菌是迄今为止感染该部位的最常见物种。关于肝病大肠杆菌（UPEC）毒力基因表达的大多数数据来自体外研究或尿路感染的鼠模型（UTI）。尚不清楚鼠模型中的基因表达与人类临床UTI期间的基因表达相比如何。缺乏这种知识可能会阻止研究重点是最高表达的毒力机制，甚至导致与人类感染无关的工作。我们的长期研究目标是了解UPEC如何在人类尿路上定居，避免免疫反应并损坏宿主。在此资助期间，目的是确定最大程度影响毒力的女性临床UTI期间三类UPEC基因的表达水平：粘附素，采集系统和毒素基因。我们的中心假设是UPEC菌株的毒力是其依从性，采集和毒素产生能力的总和。拟议工作的理由是，一旦我们确定了人类UTI期间最高表达的毒力基因，我们就可以将精力集中在针对这些高度表达目标的干预上。我们将通过完成以下特定目标来实现我们的目标：1）确定人类UTI期间表达的粘合剂； 2）确定膀胱炎所需的铁采集系统和急性肾盂肾炎所需的铁系统； 3）确定预测毒力的人类UTI中表达的毒素。进行这三个目标的预期结果将是对女性复发性和简单UTI期间UPEC菌株对毒力基因表达的精确评估。给定特定的毒力基因谱，我们将能够预测该特定菌株的毒力的潜力。这些研究的积极影响将是巨大的。我们将精确地定义UPEC菌株的性质，因为它们与共同菌株不同。我们将了解哪种毒力决定因素，包括粘附素，采集系统蛋白质和毒素在女性的临床UTI期间表达，以及它们所表达的程度。在我们项目的结论中，我们将在女性急性UTI期间明确量化UPEC菌株中的全球基因表达。这些发现对该领域至关重要，因为它们将确定UPEC在UTI期间妇女中UPEC表达的毒力决定因素，这些决定因素将阐明发病机理，对治疗靶标进行分类并突出具有疫苗发育潜力的抗原。