Abstract
To examine whether globotriaosylceramide (Gb3/CD77) is a receptor for verotoxins (VTs) in vivo, sensitivity of Gb3/CD77 synthase null mutant mice to VT-2 and VT-1 was analyzed. Although wild-type mice died after administration of 0.02 microg of VT-2 or 1.0 microg of VT-1, the mutant mice showed no reaction to doses as much as 100 times that administered to wild types. Expression analysis of Gb3/CD77 in mouse tissues with antibody revealed that low, but definite, levels of Gb3/CD77 were expressed in the microvascular endothelial cells of the brain cortex and pia mater and in renal tubular capillaries. Corresponding to the Gb3/CD77 expression, tissue damage with edema, congestion, and cytopathic changes was observed, indicating that Gb3/CD77 (and its derivatives) exclusively function as a receptor for VTs in vivo. The lethal kinetics were similar regardless of lipopolysaccharide elimination in VT preparation, suggesting that basal Gb3/CD77 levels are sufficient for lethal effects of VTs.
Highlights
Globotriaosylceramide (Gb3/CD77)2 is synthesized from lactosylceramide by ␣1,4-galactosyltransferase (Gb3/CD77 synthase, ␣1,4Gal-T)
VT-producing E. coli are considered to be causative agents of hemorrhagic colitis [7], and infections have often been associated with hemolytic uremic syndrome (HUS), which has been associated with acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia [8]
As expected, targeted disruption of the Gb3 synthase gene resulted in complete loss of the mRNA, Gb3 synthase activity, and all glycolipids belonging to the globo-series in the tissues examined
Summary
Globotriaosylceramide (Gb3/CD77)2 is synthesized from lactosylceramide by ␣1,4-galactosyltransferase (Gb3/CD77 synthase, ␣1,4Gal-T). To examine whether globotriaosylceramide (Gb3/CD77) is a receptor for verotoxins (VTs) in vivo, sensitivity of Gb3/CD77 synthase null mutant mice to VT-2 and VT-1 was analyzed. Expression analysis of Gb3/CD77 in mouse tissues with antibody revealed that low, but definite, levels of Gb3/CD77 were expressed in the microvascular endothelial cells of the brain cortex and pia mater and in renal tubular capillaries.
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