Research Project
2391485
Verotoxin (VT)-producing Escherichia coli (VTEC) have emerged as important food-borne pathogens associated with substantial illness and mortality. An estimated 20,000 cases of E. coli 0157:H7 infection occur annually in the U.S. with as many as 500 deaths. The organism infects the gastrointestinal tract causing acute hemorrhagic colitis and dissemination of VT's can lead to life-threatening systemic complications such as hemolytic uremic syndrome (HUS). Antibiotic therapy does not correlate with improved patient outcomes and a means to prevent systemic VT disease does not exist. Therefore, an antidote to neutralize disseminated VT's would be a vital new approach to prevent HUS and other systemic VT sequelae. In Phase I studies, antibodies to VT1 and VT2 of E. coli 0157:H7 were developed and tested. These antibodies neutralized VT toxicity and parenteral administration prevented both renal morbidity and mortality in a mouse disease model. Disease was prevented even when antitoxin was delayed after lethal inoculation with VTEC strains. Based on these results, a clinical prototype VT antidote will be developed and evaluated in Phase II. Studies will include development of recombinant VT antigens and corresponding antibodies and rigorous characterization of VT neutralization and antitoxin efficacy in mice. PROPOSED COMMERCIAL APPLICATION: This research is expected to provide a well characterized clinical prototype VT antitoxin. Morbidity and mortality from E. coli 0157:H7 is a growing health care concern because of increased incidence and the absence of an effective therapy.
