The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin–associated hemolytic uremic syndrome in humans and mice

Abstract

Hemolytic uremic syndrome (HUS) is a potentially life-threatening condition. It often occurs after gastro-intestinal infection with E. coli O157:H7, which produces Shiga toxins (Stx) that cause hemolytic anemia, thrombocytopenia, and renal injury. Stx-mediated changes in endothelial phenotype have been linked to the pathogenesis of HUS. Here we report our studies investigating Stx-induced changes in gene expression and their contribution to the pathogenesis of HUS. Stx function by inactivating host ribosomes but can also alter gene expression at concentrations that minimally affect global protein synthesis. Gene expression profiling of human microvascular endothelium treated with Stx implicated a role for activation of CXCR4 and CXCR7 by their shared cognate chemokine ligand (stromal cell-derived factor-1 [SDF-1]) in Stx-mediated pathophysiology. The changes in gene expression required a catalytically active Stx A subunit and were mediated by enhanced transcription and mRNA stability. Stx also enhanced the association of CXCR4, CXCR7, and SDF1 mRNAs with ribosomes. In a mouse model of Stx-mediated pathology, we noted changes in plasma and tissue content of CXCR4, CXCR7, and SDF-1 after Stx exposure. Furthermore, inhibition of the CXCR4/SDF-1 interaction decreased endothelial activation and organ injury and improved animal survival. Finally, in children infected with E. coli O157:H7, plasma SDF-1 levels were elevated in individuals who progressed to HUS. Collectively, these data implicate the CXCR4/CXCR7/SDF-1 pathway in Stx-mediated pathogenesis and suggest novel therapeutic strategies for prevention and/or treatment of complications associated with E. coli O157:H7 infection.

A novel murine infection model for Shiga toxin–producing Escherichia coli

“…We also found no hematological evidence of thrombotic disease, such as prolonged clotting time or fibrin D-dimer formation. Following systemic administration of Stx, mice that are deficient in ADAMTS13, a protease that cleaves the hemostatic von Willebrand factor, demonstrate wide strain-specific variation in the degree of microvascular thrombosis, thrombocytopenia, and hemolytic anemia (88,101). It is possible that infection by C. rodentium (λstx 2dact ) might trigger more overt microangiopathy and thus more closely resemble human HUS, in murine strains different from the C57BL/6 strain utilized here.…”

A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

“…In a murine model of shiga-toxin exposure, the CXCL12/CXCR4 interaction appeared to increase endothelial permeability (11), whereas this same interaction has also been shown to attenuate thrombin-induced endothelial permeability through phosphoinositide 3-kinase (PI3K) and Rac1 activation (10). Our previous studies have demonstrated that the analogue SDF-1α cyclic peptide known as CTCE 0214 (CTCE) improved endothelial barrier integrity in the cecal ligation and puncture (CLP) model of murine sepsis (12,13).…”

Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli–Infected Mice

“…The renal lesion in HUS patients consists of thrombi in glomerular capillaries, swelling and detachment of endothelial cells from the basement membrane (14), and extensive tubular injury (4,12). Mouse models of EHEC infection or Stx injection reproduce certain aspects of this lesion with platelet deposition in glomeruli (15,16), damaged glomerular capillaries (17), and pronounced tubular damage (7,18). In addition to severe renal damage, 20-50% of patients with HUS develop neurologic manifestations ranging from mild symptoms to coma and stroke and affecting various regions of the brain (19,20).…”