The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin-associated hemolytic uremic syndrome in humans and mice.
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.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Tania N
TN
Petruzziello-Pellegrini
Darren A
DA
Yuen
Andrea V
AV
Page
Sajedabanu
S
Patel
Anna M
AM
Soltyk
Charles C
CC
Matouk
Dennis K
DK
Wong
Paul J
PJ
Turgeon
Jason E
JE
Fish
J J David
JJ
Ho
Brent M
BM
Steer
Vahid
V
Khajoee
Jayesh
J
Tigdi
Warren L
WL
Lee
David G
DG
Motto
Andrew
A
Advani
Richard E
RE
Gilbert
S Ananth
SA
Karumanchi
Lisa A
LA
Robinson
Phillip I
PI
Tarr
W Conrad
WC
Liles
James L
JL
Brunton
Philip A
PA
Marsden
D000818:Animals; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D002648:Child; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004927:Escherichia coli Infections / Q000150:complications; D019453:Escherichia coli O157 / Q000378:metabolism / Q000472:pathogenicity; D015870:Gene Expression / Q000187:drug effects; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D046228:Microarray Analysis; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D022603:Shiga Toxins / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C501896:ACKR3 protein, human; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D022603:Shiga Toxins