Diarrheal diseases caused by enteropathogenic Gram-negative bacteria are a risk factor for morbidity and mortality in people who live in both underdeveloped and developed countries including the United States. E. coli 0157:H7 has increasingly been recognized as a cause of hemorrhagic colitis and the associated complicating condition, hemolytic uremic syndrome. E. coli 0157:H7 colonizes the intestine, intimately attaches to the intestinal mucosa in a process that requires intimin (an adhesion factor), induces hemorrhage and acute inflammation, and releases Shiga toxins (Stx) that are absorbed systemically and cause vascular damage. The process by which Stx enters the systemic circulation is poorly understood. Studies in rabbits and our preliminary data suggest that reduction of leukocyte (i.e. neutrophil) adherence by adhesion molecule inhibitors reduces the clinical severity of disease and reduces death caused by E. coli 0157:H7. It is our hypothesis that damage to the intestinal mucosa enhances passive absorption and systemic spread of Stx, resulting in enhanced Stx-induced lesions in brain and blood vessels. This damage may be caused by the bacteria, the host inflammatory response, or a combination of the two. A 3-day old pig model of E. coli 0157:H7 enteritis produced by a wild type (Stx positive, intimin positive strain) will be developed. This model will be used to determine if infection by an intimin positive, Stx negative strain of E. coli 0157:H7 or if chemically induced mucosal ulceration enhance absorption of exogenous Stx. In each of these studies, one group of pigs will be treated with a selectin inhibitor, TBC 1269, to reduce neutrophil infiltration and the results wilt be compared to the non-treated control groups to determine the contribution of neutrophils to mucosal damage and Stx absorption in a 3-day old pig model of E. coli 0157:H7 enteritis. The results of these studies will help define the mechanistic basis of Stx absorption, potentially leading to new therapeutic approaches to treating E. coli 0157:H7 enteritis and the associated systemic lesions.
