SHIGA-TOXINS: PRE-CLINICAL ANIMAL MODEL DEVELOPMENT AND THERAPEUTIC TESTING

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DESCRIPTION (provided by applicant): Shiga-like toxin producing enterohemorrhagic Escherichia coli (EHEC) strains are recognized as the most common cause of outbreaks and regional sporadic cases of bloody diarrhea and hemolytic uremic syndrome involving thousands of cases and numerous deaths annually. These bacteria are both a public health issue and a biodefense concern due to their pervasive presence in the environment and low infective dose, and they are easily transmitted with minimal sophistication. Circulating Shiga-1 and Shiga-2 toxins (Stx1, Stx2) from the infected gut are key virulence factors of this infection, giving rise to hemorrhagic colitis, hemolytic uremic syndrome and neurological complications, particularly in infants. Clinical treatment options are limited largely to intensive support because antibiotic therapy does not appear to influence outcome or disease severity, and may actually increase toxin secretion from the bacteria. This collaborative proposal is intended to further characterize clinically relevant nonhuman primate models of Shiga toxemia and hemolytic uremic syndrome, and to use these models to investigate novel therapeutic approaches expected to prevent or counteract the pathogenicity of the EHEC Shiga-like toxins. Continued development of the nonhuman primate models of Stx1 and Stx2 toxemia will encompass definition of the physiologic, metabolic, inflammatory, and coagulopathic responses using traditional clinical markers, as well as broad-based array approaches. These models will serve as the foundation for pre-clinical testing of 1) carbohydrate-linked carbosilane dendrimers that act extracellularly as toxin receptor mimetics to neutralize toxins in the circulation and prevent cytotoxicity; and 2) conjugated synthetic protein kinase C peptides that act intracellularly to neutralize toxin-induced signaling pathways that would otherwise lead to organ injury. These studies represent a collaborative effort of five laboratories who bring their respective and unique areas of expertise to converge on pre-clinical evaluation of promising therapeutics for Shiga toxemias. There are certain strains of dangerous E. coli bacteria that can infect crops or cattle, and can be transmitted through our food distribution system to thousands of households. One recent example is contamination of spinach with the E. coli O157:H7 strain that killed two people and caused illness in hundreds in the US and Canada. These bacteria are dangerous because they secrete toxins that cause severe organ damage and we do not have drugs that will counteract these toxins. This proposal uses animal models to test new drugs that are predicted to be effective in preventing or limiting the damage done by the bacterial toxins.