Intervention strategies of hemorrhagic colitis and HUS

出血性结肠炎和HUS的干预策略

• 批准号: 6615519
• 负责人: EDGAR C. BOEDEKER
• 金额: $ 28.4万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6615519
• 关键词: Escherichia coli 0157:H7; active immunization; colitis; dogs; drug screening /evaluation; hemolytic anemia; hemorrhagic disorders; immunoglobulins; laboratory rabbit; microorganism disease chemotherapy; nonhuman therapy evaluation; passive immunization; renal failure; shiga toxin; vascular endothelium

DESCRIPTION (provided by applicant): The broad aim of this proposal is to develop and utilize new and established animal model of enterohemorrhagic E. coli (EHEC) infection, in rabbits and dogs, to develop therapeutic regimens to prevent and treat EHEC disease. It is well recognized that shiga-toxin- (Stx)-producing strains of E. coli, acquired by ingestion of inadequately cooked meat, or other contaminated foods, cause hemorrhagic colitis, and may induce fatal hemolytic uremic syndrome (HUS). EHEC strains produce potent protein toxins named Shiga-like toxins (Stxs) because of their relatedness to Shiga toxin of Shigella dysenteriae. In addition, most EHEC share the ability to adhere intimately to intestinal epithelial cells by "attaching and effacing" (A/E)(7) mechanisms (Fig.2). Although EHEC attachment mechanisms may directly contribute to diarrheal disease, and may influence toxin delivery, the most severe intestinal and renal manifestations of EHEC infection result from toxin-mediated damage to vascular endothelium, with tissue edema, inflammatory infiltrates, cytokine production and vascular thrombi. At present, only supportive care is available to prevent the development of the severe, and frequently fatal, complications of EHEC infection. Strategies aimed at decreasing the toxin burden and preventing the interaction of Stxs with their endothelial receptors should prevent or ameliorate disease and damage in target organs (gut, CNS and kidney). Interventions developed in animal models can subsequently be applied to the prevention and management of EHEC disease. E. coli strain RDEC-HI9A infection of rabbits serves as the established animal model of EHEC disease for the initial intervention studies (Aims 1-4). RDEC-H19A, produced by the transfer of the toxin-converting phage H19A of an O26:H11 EHEC to the rabbit entero-pathogenic E. coli RDEC-1, is an attaching and effacing rabbit pathogen which produces high levels of Shiga-like toxin I (Stx-I), colonizes cecum and colon, and induces intestinal disease in rabbits with pathologic changes resembling human EHEC disease. Specific aims (1-4) of the proposal are to use animal models of EHEC infection to: 1). Test the ability of new toxin-receptor analogs, administered paretenteraly or enterically to prevent EHEC disease. 2). Further test the ability of passively administered immunoglobulin with anti-toxic activity to prevent EHEC disease. 3). Further examine whether antibiotic therapy has beneficial or harmful effects on the course of disease. 4). Further develop strategies for active immunization against EHEC using the Stx toxins of EHEC. 5). Specific aim 5 is to utilize canine specific A/E strains to produce new STECcapable of infecting dogs, which are susceptible to renal vascular lesions. We will transfer our labeled Stx-1 encoding phage to dog-specific A/E strains of E. coli and test their ability to produce intestinal and renal disease. The clinical studies in dogs will be performed at Kansas State University by Dr. Brad Fenwick who has described the Cutaneous and Renal Glomerular Vasculopathy (CRGV) in greyhound dogs exposed to Stx. 6). Specific Aim 6 is to extend our rabbit and dog models to be able to test similar strategies against EBEC strains expressing Stx-2. We will label and transfer toxin converting phage encoding Stx-2 to rabbit and dog specific A/E strains.

描述（由申请人提供）：本提案的主要目的是 开发和利用新建立的肠出血性大肠杆菌动物模型。 大肠杆菌（EHEC）感染，在兔子和狗，制定治疗方案， 预防和治疗肠出血性大肠杆菌病众所周知志贺毒素- （Stx）产生菌E.大肠杆菌，通过摄入不充分的 熟肉或其他受污染的食物会引起出血性结肠炎， 诱发致命溶血性尿毒综合征（HUS）。肠出血性大肠杆菌菌株产生强效 蛋白质毒素被称为志贺样毒素（Stxs），因为它们与 志贺菌的滋贺毒素。此外，大多数肠出血性大肠杆菌 通过"附着和去除"紧密粘附于肠上皮细胞 （A/E）（7）机制（图2）。虽然肠出血性大肠杆菌的附着机制可以直接 有助于肠道疾病，并可能影响毒素的传递，最 肠出血性大肠杆菌感染的严重肠道和肾脏表现是由 毒素介导的血管内皮损伤，伴组织水肿，炎性 浸润、细胞因子产生和血管血栓。目前只有 提供支持性护理，以防止严重的发展， 肠出血性大肠杆菌感染的并发症往往是致命的。的战略 减少毒素负担，防止Stx与它们的相互作用， 内皮受体可以预防或改善靶细胞的疾病和损伤， 器官（肠道、CNS和肾脏）。在动物模型中开发的干预措施可以 随后将其应用于EHEC疾病的预防和管理。e. 大肠杆菌菌株RDEC-HI9A感染家兔作为建立的动物 初步干预研究的肠出血性大肠杆菌疾病模型（目标1 - 4）。 RDEC-H19A，通过转移一种细菌的毒素转化噬菌体H19A而产生。 O26：H11 EHEC对家兔肠致病性E. coliRDEC-1，是一种附着于 并清除产生高水平志贺样毒素I的兔病原体 （Stx-I），定殖于盲肠和结肠，并在兔中诱导肠道疾病 其病理变化类似于人类肠出血性大肠杆菌病。具体目标（1 - 4） 建议使用肠出血性大肠杆菌感染动物模型：1）。测试 新的毒素受体类似物的能力， 预防肠出血性大肠杆菌病。2）。进一步测试被动的能力 给予具有抗毒性活性的免疫球蛋白以预防EHEC疾病。 3）。进一步检查抗生素治疗是否有益或有害 对病程的影响。4）。进一步制定战略， 使用EHEC的Stx毒素进行针对EHEC的免疫。5）。具体目标5是 利用犬特异性A/E菌株产生能够感染 狗，这是容易受到肾血管病变。我们将把我们的 标记的Stx-1编码噬菌体与狗特异性的E.大肠埃希菌及检测 他们产生肠道和肾脏疾病的能力。临床研究在 狗将在堪萨斯州立大学由博士布拉德芬威克谁拥有 描述了灰狗的皮肤和肾脏肾小球血管病变（CRGV） 狗暴露于Stx。6）。具体目标6是扩展我们的兔子和狗模型 能够测试针对表达Stx-2的EBEC菌株的类似策略。我们 将编码Stx-2的毒素转化噬菌体标记并转移至兔和狗 A/E菌株。