HUS Pathogenesis & clinical Outcome in an in vivo model

点击翻译按钮获取中文摘要

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.