Shiga toxin-associated hemolytic uremic syndrome: advances in pathogenesis and therapeutics

Abstract

Purpose of review: Diarrhea-associated hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) continues to be an important public health threat worldwide. Specific therapies are lacking and patient care remains largely supportive. This review discusses the lessons learned from recent events and summarizes key advances made toward understanding the basic mechanisms involved in the pathogenesis of typical HUS.

Recent findings: The recent German outbreak of a hybrid organism resulted in an unprecedented number of HUS cases and drastically changed the face of typical (diarrhea-associated) HUS. New findings on the roles of complement and the CXCR4/SDF-1 pathway in HUS pathogenesis are summarized and novel therapeutic strategies are highlighted.

Summary: A better understanding of STEC-mediated HUS underlies improved therapeutic approaches. New studies of the mechanistic basis of the disease, together with patient-based studies, have led to key findings with important clinical implications.

FIGURE 1

Molecular mechanisms of Shiga toxin (Stx) pathobiology. Stx inactivates host ribosomes by removing a specific adenine residue from the 28S rRNA, thus inhibiting protein synthesis. At concentrations that have only minor effects on global protein synthesis, Stx causes changes in gene expression and endothelial cell phenotype.

FIGURE 2

Manganese blocks intracellular transport of Shiga toxin (Stx). Receptor-bound Stx is internalized by endocytosis and is transported retrogradely to the Golgi and endoplasmic reticulum (ER). The A subunit becomes activated upon cleavage and is translocated to the cytosol where it exerts its enzymatic activities. Manganese blocks retrograde transport of the toxin from the endosome to the Golgi leading to lysosomal degradation, and thereby disrupts Stx pathogenesis. Gb3, globotriaosylceramide. Adapted with permission [42].

FIGURE 3

The contribution of the CXCR4/SDF-1 pathway to Shiga toxin (Stx) pathophysiology. Stx induces changes in endothelial gene expression and phenotype. Among the changes observed is detachment of the endothelium to expose the underlying basement membrane, subendothelial edema, and increased platelet adhesion. In vivo, this is accompanied by thrombocytopenia and red blood cell (RBC) fragmentation. CXCR4 and its ligand, SDF-1, are upregulated by Stx both in vitro and in vivo. Inhibition of CXCR4/SDF-1 interaction in vitro using plerixafor prevents Stx-mediated platelet adhesion to the endothelium under flow conditions. In vivo, plerixafor restores platelets to basal levels in an animal model of Stx challenge, and significantly attenuates Stx-mediated mortality. Individuals infected with E. coli O157:H7 exhibit elevated SDF-1 levels prior to onset of clinical features of hemolytic uremic syndrome. Taken together, these findings implicate an important role for the CXCR4/SDF-1 pathway in Stx-mediated pathogenesis. Gb3, globotriaosylceramide.