Clinical Investigation of E.coli Biofilm Formation in the Human Bladder

描述（由申请人提供）：在美国，每年有3000多万膀胱导管插入500多万患者体内。导管插入患者每天以5%的速率获得菌尿，并有导管相关性尿路感染（CITTI）和菌血症的风险。粘附微生物的导管相关生物膜加上分泌的多糖基质是CIMTI发病机制的核心。生物膜中的生物体与它们的寄生虫对应物相比，对抗菌剂和宿主防御的敏感性降低。因此，使用标准的抗微生物剂来预防膀胱炎经常导致膀胱定植有耐药植物群。E.大肠杆菌是大肠杆菌感染的最常见病原体，已被用作体外研究生物膜形成的模式生物。然而，生物膜的形成以前没有研究过导尿管在人类膀胱。本项目的具体目标是：（1）确定E.大肠杆菌体外表达，在体内由E.大肠杆菌83972（一种无毒菌株）在人膀胱内留置导尿管表面的感染，以及（2）进行临床试验以确定是否删除Aim 1中鉴定的基因可以防止大肠杆菌83972（一种无毒菌株）在膀胱内留置导尿管表面的感染。大肠杆菌从寄居在人类膀胱中的导尿管中分离出来。这些研究将确定的遗传毒力因子，这是一个新的干预称为毒力因子修饰的潜在目标。毒力因子修饰的概念，其中化合物被开发以抑制毒力而不杀死微生物，对于预防和治疗抗真菌感染特别有吸引力。通过削弱病原体在膀胱中形成生物膜的能力来解除病原体可能会削弱它们的持久性，使它们更容易受到宿主防御的影响。拟议的研究与公共卫生的相关性：在美国，CIMTI是一种非常常见的感染，是医院感染的主要原因之一。抗凝血剂也会干扰长期插管人群的健康和福祉。对于需要持续使用导管的患者，目前尚无有效的策略来预防急性呼吸道感染。确定导致ESTTI所需的基因将导致预防这种疾病的新策略。

DESCRIPTION (provided by applicant): Each year more than 30 million bladder catheters are inserted into more than 5 million patients in the United States. Catheterized subjects acquire bacteriuria at the rate of 5% per day and are at risk for catheter-associated urinary tract infection (CAUTI) and bacteremia. The catheter-associated biofilm of adherent organisms plus secreted polysaccharide matrix is central to the pathogenesis of CAUTI. Organisms in biofilms have reduced susceptibility to antimicrobial agents and to host defenses compared to their planktonic counterparts. Thus, using standard antimicrobial agents to prevent CAUTI frequently leads to bladder colonization with resistant flora. E. coli, the most common causative agent of CAUTI, has been used as a model organism to study biofilm formation in vitro. However, biofilm formation has not previously been studied on urinary catheters in human bladders. The specific aims of this project are (1) to determine whether genes described as essential to bio- film formation by E. coli in vitro are expressed in vivo by E. coli 83972 (a nonvirulent strain) on the surface of urinary catheters dwelling in human bladders, and (2) to perform a clinical trial to determine whether deleting the genes identified in Aim 1 prevents E. coli from colonizing urinary catheters that are dwelling in human bladders. These studies will identify the genetic virulence factors of CAUTI which are potential targets for a new intervention called virulence factor modification. The concept of virulence factor modification, in which compounds are developed to inhibit virulence without killing the microorganism, is particularly attractive for prevention and treatment of CAUTI. Disarming pathogens by impairing their ability to form a biofilm in the bladder may impair their persistence and render them more susceptible to host defenses. Relevance of the proposed research to public health: CAUTI is an extremely common infection, one of the leading causes of nosocomial infection in the United States. CAUTI also interferes with the health and well-being of chronically catheterized populations. No effective strategy exists to prevent CAUTI in persons who require ongoing catheter use. Identifying genes that are required to cause CAUTI will lead to new strategies to prevent this illness.