HUS Pathogenesis & clinical Outcome in an in vivo model

描述（由申请人提供）：本提案的总体目标是进一步开发和验证我们最近描述的肠出血性大肠杆菌（EHEC）感染的新动物模型。我们将使用我们实验室开发的模型来研究溶血性尿毒症综合征（HUS）的发病机制，重要的是制定预防和治疗肠出血性大肠杆菌疾病的治疗方案。产生志贺毒素（Stx）的大肠杆菌（STEC）菌株是通过摄入未煮熟的肉类或其他受污染的食物获得的。人际传播也是可能的。这些细菌引起出血性结肠炎，并可诱发以微血管致病性溶血性贫血、血小板减少症和急性肾功能衰竭为特征的致命性溶血性尿毒综合征。O157:H7大肠杆菌感染的严重性体现在以下事实：约6%的感染者，特别是儿童，作为原发性肠出血性大肠杆菌感染的后遗症发展为溶血性尿毒综合征，约25%的患者发展为进行性肾脏疾病。肠出血性大肠杆菌菌株产生一种名为志贺样毒素（Stx1和Stx2）的强效蛋白毒素，与志贺痢疾杆菌的志贺毒素密切相关。肠出血性大肠杆菌感染最严重的肠道和肾脏表现是毒素介导的血管内皮损伤，导致组织水肿、炎症浸润、促炎细胞因子产生、凝血途径诱导并导致血管血栓。目前，只有支持性护理可用于预防肠出血性大肠杆菌感染的严重且经常致命的并发症的发展。大肠杆菌O157:H7和其他产血性大肠杆菌引起血性腹泻、溶血性尿毒综合征和血小板减少症的致病过程仍然不完全清楚，部分原因是缺乏合适的动物模型。将制定有针对性的干预策略来治疗溶血性尿毒综合征，并帮助确定溶血性尿毒综合征发病机制的可操作性。该提案的具体目标1和2是通过以下方式进一步表征荷兰带（DB）兔EHEC感染模型：1)确定EHEC诱导的兔溶血性尿毒综合征中可操作的重要病理生理事件，并采用治疗方式中断这些导致溶血性尿毒综合征的不良事件；2)检测被动给药免疫球蛋白或靶向单克隆抗体预防肠出血性大肠杆菌疾病的能力。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to further develop and validate a new animal model of enterohemorrhagic E. coli (EHEC) infection that we recently characterized. We will use this model developed in our laboratory to study pathogenesis of hemolytic uremic syndrome (HUS) and importantly to develop therapeutic regimens to prevent and treat EHEC disease. Shiga-toxin (Stx)-producing E. coli (STEC) strains are acquired by ingesting inadequately cooked meat or other contaminated foods. Person-to-person transmission is also possible. These bacteria cause hemorrhagic colitis and may induce fatal HUS characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The serious nature of E. coli O157:H7 infection is illustrated by the fact that ~6% of those infected, particularly children, develop HUS as a sequela of the primary EHEC infection and ~ 25% of these patients develop progressive renal disease. EHEC strains produce potent protein toxins named Shiga-like toxins (Stx1 and Stx2) that are closely related to Shiga toxin of Shigella dysenteriae. The most severe intestinal and renal manifestation of EHEC infection result from toxin-mediated damage to vascular endothelium, with tissue edema, inflammatory infiltrates, proinflammatory cytokine production, coagulation pathway induction and resulting vascular thrombi. At present, only supportive care is available to prevent the development of the severe, and frequently fatal, complications of EHEC infection. The pathogenic process by which E. coli O157:H7 and other STEC evoke bloody diarrhea, HUS, and thrombocytopenia remains incompletely understood in part due to the lack of a suitable animal model. Targeted intervention strategies will be developed to treat HUS as well as help define mechanisms operable in the pathogenesis of HUS. Specific Aims 1 and 2 of the proposal are to further characterize the Dutch Belted (DB) rabbit model of EHEC infection by 1) Defining important pathophysiologic events operable in EHEC-induced HUS in rabbits and employ therapeutic modalities to interrupt these adverse events leading to HUS; 2) Testing the ability of passively administered immunoglobulin or targeted monoclonal antibodies to prevent EHEC disease. Enterohemorrhagic E. coli (EHEC) O157:H7 is the most common infectious cause of bloody diarrhea in the U.S. and approximately 6% of those infected, particularly children, develop hemolytic uremic syndrome (HUS) as a sequela of the primary EHEC infection. The overall goal of this proposal is to further develop and validate a new animal model of EHEC infection that we recently characterized. We will use this model to study the pathogenesis of HUS and importantly to develop therapeutic regimens to prevent and treat EHEC disease.