MI005-04 Murine Models of Hemolytic Uremic Syndrome (HUS) - Completed

The hemolytic uremic syndrome (HUS) is characterized by microangiopathis anemia, thrombocytopenia and acute renal failure. HUS is most commonly associated with an antecedent infection with enterohemorrhagic E.coli (EHEC). The production of Shiga toxin (Stx) by EHEC strains plays a key role in the pathogenesis of HUS. Stx itself binds to the membrane neutral glycolipid globotriaosycleramide (Gb3). The development of small animal models of EHEC infection would greatly aid the development of novel therapeutic agents and preventative strategies for HUS. Because of their small size and wealth of genetic, immunologic and physiologic knowledge available, mice make attractive models for a variety of infectitious agents. Currently available models of EHEC infection donot accurately reflect the entirety of clinical manifestations of human HUS. We propose to develop a murine model of HUS induced by EHEC infection employing an alpha-galactosidase A mutany mourse strain that accumulates Gb3 in tissues. In three years we will deliver: 10information on the distribution of Stx binding sites in alpha-galactosidase A mutant mice, 2) information on the sensitivity of this strain to purified Stx and Stx-producing E.coli, and 3) information on the ability of lipopolysaccharide to influence the appearance of disease in this model.

Publications:

A Germ-Free Mouse Model of Renal Disease Due to Enterohemorrhagic Escherichia Coli

A Reproducible Scoring System for Quantification of Histologic Lesions of Inflammatory Disease in Mouse Gastric Epithelium

Pathogenesis of Renal Disease Due to Enterohemorrhagic Escherichia coli in Germ-Free Mice

The Pathogenesis of Renal Disease Due to Enterohemorrhagic E. coli in Germ
Free Mice