TREATMENT INTERVENTIONS FOR HEMORRHAGIC COLITIS

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DESCRIPTION The broad aim of this application is to use a new animal model of enterohemorrhagic Escherichia coli (EHEC) infection to develop prophylactic and therapeutic regimens to prevent and treat EHEC disease. The most severe intestinal and renal manifestations result from toxin-mediated damage to vascular endothelium, with tissue edema, inflammatory infiltrates, cytokine production and vascular thrombi. Strategies will be focused on preventing, or limiting, the interaction of Shiga-like toxins (SLTs) with the vascular endothelium by neutralizing toxin within the vascular compartment by: binding toxin in the gut lumen; eliminating the toxin-producing organisms; and/or inhibiting the action of pro-inflammatory cytokines. At present, there is no vaccine for EHEC, neither are there established effective interventions to prevent or treat hemorrhagic colitis if exposure to EHEC occurs. Only supportive care is available to prevent the development of the severe complications of EHEC infection. Strategies aimed at preventing the inter-action of SLTs with their endothelial receptors should prevent or ameliorate damage in target organs (gut, CNS and kidney) Escherichia coli strain RDEC-H19A infection of rabbits will serve as the animal model of EHEC disease for these studies. This RDEC H19A, produced by the transfer of the toxin-converting phage H19A of an 026:H11 EHEC to the rabbit entero-pathogenic E. coli RDEC-1, is an attaching and effacing rabbit pathogen. This strain produces high levels of Shiga-like toxin I (SLT-I), colonizes cecum and colon, and induces intestinal disease in rabbits with pathologic changes resembling human EHEC disease. Our recent work demonstrates that the genes for attaching/effacing interactions in RDEC-I are highly homologous to those in enterohemorrhagic Escherichia coli strains; both of 026:H11 and 0157:7 serotypes. Preliminary data indicate that protection against the vascular complications of this infection can be prevented by systemic anti-SLT antibody, or by mucosal immunity to the pathogen. Specific aims (1-5) of the application are to use this animal model of infection to: test the ability of passively administered immunoglobulin with anti-toxic activity to prevent EHEC disease; test the ability of intraluminal toxin-receptor analogs to prevent EHEC disease; determine whether antibiotic therapy has beneficial or harmful effects on the course of disease; determine whether anti-inflammatory strategies, in particular IL-I receptor antagonist (IL-lra), can alter the disease; develop strategies for active immunization against EHEC using the toxins, adhesions and somatic antigens of EHEC; and to extend the animal model to test similar strategies against EHEC strains expressing SLT-II. We hypothesize, based on preliminary data, that approaches designed to limit toxin interactions with vascular endothelium can best be developed in an animal model. These strategies could subsequently be applied to the management of EHEC infection.