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

描述（由申请人提供）：在美国，每年有超过3000万例膀胱导尿管插入超过500万例患者。导尿的受试者以每天5%的比率获得细菌尿，并有导尿相关尿路感染（CAUTI）和菌血症的风险。附着生物的导管相关生物膜加上分泌的多糖基质是CAUTI发病机制的核心。与浮游生物相比，生物膜中的生物对抗菌剂和宿主防御的敏感性降低。因此，使用标准抗菌剂预防CAUTI经常导致膀胱定植耐药菌群。大肠杆菌是CAUTI最常见的病原体，已被用作体外研究生物膜形成的模式生物。然而，生物膜的形成还没有研究导尿管在人类膀胱。该项目的具体目的是：(1)确定体外大肠杆菌生物膜形成所必需的基因是否在体内由大肠杆菌83972（一种无毒性菌株）在驻留在人类膀胱中的导尿管表面表达，以及(2)进行临床试验，以确定删除Aim 1中鉴定的基因是否可以阻止大肠杆菌在驻留在人类膀胱中的导尿管中定植。这些研究将确定CAUTI的遗传毒力因子，这是一种称为毒力因子修饰的新干预的潜在目标。毒力因子修饰的概念，即开发出在不杀死微生物的情况下抑制毒力的化合物，对预防和治疗CAUTI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它们的武装，可能会损害它们的持久性，使它们更容易受到宿主防御的影响。拟议研究与公共卫生的相关性：CAUTI是一种极其常见的感染，是美国医院感染的主要原因之一。CAUTI还会干扰长期导尿人群的健康和福祉。目前还没有有效的策略来预防需要持续使用导管的患者的CAUTI。确定导致CAUTI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.