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: 8183135
• 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
• 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/8183135
• 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; Pattern; 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

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because urinary tract infection (UTI) remains a significant source of morbidity. Most recently there were 8.2 million physician visits, over 1.7 million emergency room visits, and 366,000 hospitalizations of both men and women in the United States for UTI, at an annual cost of 3.4 billion dollars. These frequencies place UTIs first among kidney and urologic diseases in terms of total cost. This is relevant to NIH's mission because precisely defining the mechanism by which E. coli infects the urinary tract will lead to therapies that may extend healthy life by reducing the burden of these infections.

描述（由申请人提供）：泌尿道是最常见的细菌感染部位之一，大肠杆菌是迄今为止感染该部位最常见的物种。大多数关于尿路致病性大肠杆菌（UPEC）毒力基因表达的数据来自体外研究或尿路感染（UTI）小鼠模型。目前尚不清楚小鼠模型中的基因表达与人类临床尿路感染中的基因表达如何比较。缺乏这方面的知识可能会阻碍对高度表达的毒力机制的研究，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如何在人类尿道中定居，避免免疫反应，并损害宿主。在此资助期间的目标是确定三种类型的UPEC基因的表达水平，在临床尿路感染的妇女最影响毒力：粘连素，铁获取系统和毒素基因。我们的中心假设是，UPEC菌株的毒力是其粘附能力、铁获取能力和毒素产生能力的总和。这项工作的基本原理是，一旦我们确定了人类尿路感染期间最高度表达的毒力基因，我们就可以集中精力针对这些高度表达的目标进行干预。我们将通过完成以下具体目标来实现我们的目标：1)确定人类尿路感染期间表达的粘附素；2)确定膀胱炎和急性肾盂肾炎所需的铁获取系统；3)确定人类尿路感染过程中表达的毒素，预测毒性。实施这三个目标的预期结果将是准确评估upc菌株在妇女复发性和非复杂性尿路感染期间的毒力基因表达。给定特定的毒力基因谱，我们将能够预测该特定菌株的潜在毒力。这些研究的积极影响将是巨大的。我们将精确地定义一个UPEC菌株的性质，因为它们不同于共生菌株。我们将了解哪些毒力决定因素，包括粘附素、铁获取系统蛋白和毒素在女性临床尿路感染期间表达，以及表达程度。在我们的项目结束时，我们将明确量化妇女急性尿路感染期间UPEC菌株的全球基因表达。这些发现对该领域至关重要，因为它们将确定妇女尿路感染期间upc表达的毒力决定因素，从而阐明发病机制，分类治疗靶点，并突出具有疫苗开发潜力的抗原。