The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin–associated hemolytic uremic syndrome in humans and mice
Tania N. Petruzziello-Pellegrini, … , James L. Brunton, Philip A. Marsden
Tania N. Petruzziello-Pellegrini, … , James L. Brunton, Philip A. Marsden
Published January 9, 2012
Citation Information: J Clin Invest. 2012;122(2):759-776. https://doi.org/10.1172/JCI57313.
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Research Article Nephrology

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 gastrointestinal 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.

Authors

Tania N. Petruzziello-Pellegrini, Darren A. Yuen, Andrea V. Page, Sajedabanu Patel, Anna M. Soltyk, Charles C. Matouk, Dennis K. Wong, Paul J. Turgeon, Jason E. Fish, J.J. David Ho, Brent M. Steer, Vahid Khajoee, Jayesh Tigdi, Warren L. Lee, David G. Motto, Andrew Advani, Richard E. Gilbert, S. Ananth Karumanchi, Lisa A. Robinson, Phillip I. Tarr, W. Conrad Liles, James L. Brunton, Philip A. Marsden

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Figure 11

Circulating SDF-1 levels in HUS patients.

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Circulating SDF-1 levels in HUS patients. SDF-1 levels were measured in ...
SDF-1 levels were measured in plasma samples from individuals infected with E. coli O157:H7. (A) Infected samples obtained from patients with uncomplicated O157:H7 infection within 4 days after the onset of diarrhea (n = 36). Horizontal bars indicate the median values, boxes indicate 25th to 75th percentiles, and whiskers indicate the minimum and maximum values. Pre-HUS, samples collected prior to HUS diagnosis in those individuals who later progressed to HUS (n = 7); HUS, samples collected on the day of HUS diagnosis (n = 22). *P < 0.05. (B) SDF-1 levels over the course of E. coli O157:H7–mediated illness. Each line represents 1 patient, and the last data point for each patient was obtained on the day of HUS diagnosis.