Digestive Health Center

  • Inflammatory and Diarrheal Diseases

    Alison A. Weiss, PhD
    Professor
    Department of Molecular Genetics, Biochemistry and Microbiology

    Description of Research

    Dr. Weiss focuses on host pathogen interactions with regard to infectious diarrhea caused by E. coli O157:H7. Disease caused by E. coli O157:H7 is characterized by diarrhea, hemorrhagic colitis, and the potentially fatal complication, hemolytic uremic syndrome. Shiga toxin (Stx) is a major virulence factor of E. coli O157:H7. Two major antigenic variants of Shiga toxin, Stx1 and Stx2, share 55% amino acid homology. Strains of O157:H7 can produce Stx1, Stx2, or both; however, the ability to produce Stx2 has been associated with progression to severe disease, including hemolytic uremic syndrome. The importance of Stx2 in life-threatening disease has been definitively established in recent studies demonstrating that administration of purified Stx2 led to the development of HUS in experimental models, while an equivalent dose of Stx1 did not. We have shown that Stx1 and Stx2 display different receptor binding preferences, and these differences likely mediate the differences in toxin potency. While it is clear that Stx2 can induce cellular death, it is also not clear that cellular death is required for development of hemolytic uremic syndrome. In recent studies we have shown that Stx promotes activation of cellular signaling pathways in human umbilical vascular endothelial cells, leading to release of Von Willebrand factor minutes after toxin treatment, a time frame too short to be due to protein synthesis inhibition. Surface expression of Von Willebrand factor is a signal for endothelial damage, and inappropriate release of Von Willebrand factor could be an initiating factor in development of the platelet activation that causes the thrombocytopenia seen in hemolytic uremic syndrome. 

    Collaborations and Core Use

    Dr. Weiss collaborates with Dr. Cohen on the structure of Shiga toxin and its receptor preferences. Anticipated use of Cores: Integrative Morphology and Gene and Protein Expression Cores.

 
  • Research image.

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    Research image.

    Pk binding sites in the Shiga toxin 1 (Stx1) B-subunit. Bottom view of crystal structure of Stx1 B-pentamer bound to trisaccharide component of globotriaosylceramide (Pk) with the 3 Pk binding sites colored red, purple, and orange in a single monomer. Figure from Biochemistry, 2010;49:1649-57.