Hemolytic uremic syndrome (HUS) is defined by a characteristic set of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Shiga toxin produced by EHEC activates complement via the alternative pathway. It also binds to Factor H thus reducing its cofactor activity contributing as a major virulence factor involved in the pathogenesis of EHEC associated HUS (eHUS). Complement pathways unveil a high degree of amplification that necessitates regulation to prevent attack of self. Membrane bound regulator CD59 inhibits complement activation on host cell surface by binding to C8 and C9 thus inhibiting terminal complement complex (TCC) assembly. Shiga Toxin 2 reduces CD59 expression on human renal tubular epithelial and glomerular endothelial cells. Thus complement plays a crucial role in the execution of innate immunity which has been well characterized in the blood, but requires attention for its evidence in gut.
Following ingestion, EHEC migrates through the gut attaching to the mucosal epithelial cells of the large intestine. Shiga toxins and other virulence factors however translocate into the circulation, affecting vulnerable target organs like kidneys and the brain. Although the mechanism has been widely investigated in the terminal zone of action, there remain ample possibilities to investigate its action in the gut which often leads to bloody diarrhea and thus destruction of gut mucosa.
Our laboratory proposes a multidisciplinary approach to advance our understanding of the interactions of Shiga toxin and other associated EHEC virulence factors not just in the circulation, but also in the gut. Evaluation of alteration in expression of regulators of complement cascade remains our major thrust area in the project. Investigation into these aspects of HUS may prove helpful in developing new interventions for improving clinical outcomes in patients with HUS.
