Pathogenic E. coli are a major cause of human diseases. Escherichia coli 0157:H7 is an """"""""emerging infectious disease"""""""" responsible for outbreaks of food-borne illness and is the leading cause of hemolytic uremic syndrome (HUS), acute renal failure in young children. There is growing evidence that inflammatory mediators are induced in the host by E. coli 0157:H7 LPS and Shiga toxins and that both are required to cause HUS. In addition, Shiga toxins (Stx1, Stx2) produced by E. coli 0157:H7 are required for the vascular complications in HUS. At present, no effective treatments are available for E. coli 0157:H7. Thus, our long-term goal is to develop therapeutic modalities based on mechanisms by which LPS, Stx1, and Stx2 cause disease. The short-term goal is to define host inflammatory responses to E. coli LPS and Shiga toxins. In the present study, gene microarrays are employed to delineate the inflammatory response to LPS and Stx2 in mouse models of kidney and lung disease. In addition, the effectiveness of anti-inflammatory adenosine A2A receptor agonists will be tested in the murine model of LPS plus Stx1/Stx2-induced inflammation. These latter studies are based on two recent findings: 1) that a pronounced inflammatory phase is associated with LPS/Stx2 response in the kidneys of mice, and 2) that A2A receptor agonists exhibit a protective role in LPS-dependent lung inflammation and prevent LPS-induced mortality. Application of the anti-inflammatory A2A receptor agonists to E. coli 0157:H7-associated disease will be further defined using A2A receptor deficient mice and adoptive bone marrow transfer to determine the role of circulating inflammatory cells in this disease. ? ?
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| Keepers, Tiffany R; Psotka, Mitchell A; Gross, Lisa K et al. (2006) A murine model of HUS: Shiga toxin with lipopolysaccharide mimics the renal damage and physiologic response of human disease. J Am Soc Nephrol 17:3404-14 |
