Shiga toxin-producing E. coli O157:H7 (STEC) is an emerging bacterial pathogen responsible for foodborne outbreaks of disease in the United States resulting in significant morbidity and mortality. The potent Shiga toxins (Stx1 and Stx2) together with pro-inflammatory bacterial lipopolysaccharide (LPS) are responsible for much of the disease burden and kidney damage known as the hemolytic uremic syndrome (HUS). Currently, no specific therapies are available for treatment of this disease. The primary goal of this project is to identify and test new therapeutics for STEC-associated infection and HUS. The long-range goal is to develop new therapies for clinical use that will reduce, eliminate, or prevent STEC related disease. The current focus is on interrupting the inflammation and cellular stress that take place in the kidneys following exposure to Shiga toxins plus LPS. Our hypothesis is that the most effective therapies for HUS will be those that interrupt the dictinct actions of both Shiga toxin and LPS. Thus, specific anti-inflammatory agents such as adenosine receptor agonists will be studied in detail to protect the host from the inflammation-mediated morbidity triggered by LPS. In addition, potent inhibitors of cellular ribotoxic stress will also be examined for protection against morbidity and mortality caused by the Shiga toxins. New forms of adenosine compounds with desirable pharmacological properties will be synthesized and examined for maximum efficacy in cell cultures and in a newly developed murine model of HUS that exhibits the hallmarks of HUS in humans. The most promising of the adenosine compounds will then be produced in larger quantity to complete pre-clinical testing. In addition, newly identified agents that target the Shiga toxin-induced ribotoxic stress signal transduction pathways will be examined for protection against progression to HUS. Finally, specific combinations of adenosine receptor agonists and inhibitors of cellular stress pathways will be studied for synergistic efficacy in post-exposure therapy of Shiga toxin and LPS. This project brings together medical scientists, chemists, and physicians from leading academic research centers and biotechnology industry in an effort to make available new and effective treatments for STEC-associated disease.
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