Intervention strategies of hemorrhagic colitis and HUS

出血性结肠炎和HUS的干预策略

基本信息

批准号：
7263653
负责人：
EDGAR C. BOEDEKER
金额：
$ 23.31万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7263653
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

项目摘要

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）：该提案的广泛目的是开发和利用Enterohemorrhagic E.的新动物模型。大肠杆菌（EHEC）感染，兔子和狗，开发治疗方案预防和治疗EHEC疾病。众所周知，志贺 - 毒素 - （STX） - 大肠杆菌的产生菌株，通过摄入不足而获得煮熟的肉或其他受污染的食物会导致出血性结肠炎，可能诱导致命的溶血性尿毒症综合征（HUS）。 EHEC菌株产生有效的蛋白质毒素称为志公式毒素（STXS），因为它们与 Shigella dysenteriae的Shiga Toxin。此外，大多数EHEC都有能力通过“附着和esfacing”亲密地粘附在肠上皮细胞上（A/E）（7）机制（图2）。尽管EHEC依恋机制可能直接促进腹泻病，并可能影响毒素递送，最大 EHEC感染的严重肠道和肾脏表现。毒素介导的对血管内皮的损伤，炎症，炎症浸润，细胞因子产生和血栓血栓。目前，只有可以使用支持护理来防止严重的发展，并且经常致命的EHEC感染并发症。策略针对减轻毒素负担并防止STX与其相互作用内皮受体应预防或改善靶标的疾病器官（肠道，中枢神经系统和肾脏）。动物模型中制定的干预措施可以随后应用于预防和管理EHEC疾病。 E. 大肠杆菌菌株RDEC-HI9A兔子感染是已建立的动物 EHEC疾病模型的初步干预研究（AIMS 1-4）。 RDEC-H19A，由毒素转化的噬菌体H19A的转移产生 O26：H11 EHEC到兔肠道病原体大肠杆菌RDEC-1，是一个附件并在产生高水平的shiga样毒素I的兔病原体上（STX-I），在盲肠和结肠定殖，并在兔子中诱导肠道疾病随着病理变化类似于人类EHEC疾病。具体目的（1-4）该提案是将EHEC感染的动物模型用于：1）。测试新型毒素受体类似物的能力，掌握或 inter intel in in in in in in in in in in in the EHEC疾病。 2）。进一步测试被动的能力给予具有抗毒活性的免疫球蛋白，以预防EHEC疾病。 3）。进一步检查抗生素疗法是有益还是有害对疾病进程的影响。 4）。进一步制定活跃的策略使用EHEC的STX毒素对EHEC进行免疫。 5）。具体目标5是利用犬类特异性的A/E菌株产生可感染的新的感染狗，容易患肾血管病变。我们将转移我们的标记的STX-1编码噬菌体到大肠杆菌的狗特异性A/E菌株和测试它们产生肠道和肾脏疾病的能力。临床研究狗将由Brad Fenwick博士在堪萨斯州立大学进行描述了灵狮的皮肤和肾肾小球血管病（CRGV）暴露于STX的狗。 6）。特定目标6是扩展我们的兔子和狗模型能够针对表达STX-2的EBEC菌株测试类似的策略。我们将标记和转移毒素转换编码STX-2到兔子和狗的噬菌体特定的A/E菌株。