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susceptibility to intoxication by Stx requires that Gb 3 be localized to lipid rafts
( Falguieres et al., 2001 ; Kovbasnjuk et al., 2001 ; Hanashima et al., 2008 ). It is
therefore conceivable that Gb 3 -positive and/or -negative intestinal epithelial cells
take up Stx but are not intoxicated by them.
Once in the systemic circulation, Stx can reach target organs such as the brain
and kidney, where it can induce life-threatening disease. Data are inconclusive as
to whether Stx circulates freely in the serum and/or is carried by blood cells to target
organs. While small amounts of free Stx have been detected in HUS patients, Stx
has been shown to bind in vitro to a variety of blood components including PMNs,
platelets, monocytes, and red blood cells (RBCs) ( Bitzan et al., 1994 ; van Setten
et al., 1996 ; Te Loo et al., 2001b ; Ghosh et al., 2004 ; Stahl et al., 2006 ), and Stx-
positive PMNs have also been detected in patients with HUS ( Brigotti et al., 2011 ).
HUS is a microangiopathic disorder featuring deposition of thrombi rich in
fibrin and platelets in the renal microvasculature (reviewed in Blackall and Marques
(2004) ). Glomerular capillaries are occluded by these thrombi resulting in isch-
emic damage to the endothelium. Endothelial expression of IL-8, fractaline, and
monocyte chemotactic protein (MCP-1) promotes endothelial adherence by leu-
kocytes in the presence of Stx ( Zoja et al., 2002 ; Geelen et al., 2008 ; Zanchi et al.,
2008 ). Furthermore, PMNs are capable of transferring toxin to endothelial cells
( Te Loo et al., 2000 ; Brigotti et al., 2010 ). Stx has been found bound to platelets
( Stahl et al., 2006 ), PMN-platelet complexes, and monocyte-platelet complexes in
HUS patients ( Stahl et al., 2009 ). The toxin also binds to fibrinogen and promotes
platelet aggregation and adherence to endothelial cells ( Karpman et al., 2001 ), and
thus could contribute to the fibrin-rich clots associated with HUS. Finally, Stx can
induce the expression of tissue factor on monocytes, and trigger the release of
monocyte-derived microparticles, which may contribute to thrombosis by increas-
ing the amount of circulatory tissue factor ( Murata et al., 2006 ; Stahl et al., 2009 ).
Renal vascular damage is a prominent feature of HUS, and kidney failure
is one of the most serious sequelae during EHEC infection (reviewed in Obrig
and Karpman (2012) ). A plausible hypothesis is that renal pathology results
from pro-thrombotic damage to Gb 3 -expressing microvascular endothelium of
the kidney by circulating Stx, in particular Stx2 ( Obrig and Karpman, 2012 ).
Indeed, Stx has been detected in kidney tissue from patients with HUS ( Uchida
et al., 1999 ; Chaisri et al., 2001 ). A possible reason the kidney is specifically
targeted may be an elevated Gb 3 density in that tissue, because cultured human
renal microvascular endothelial cells express 50-fold more Gb 3 than human
umbilical vein endothelial cells ( Obrig et al., 1993 ). Human glomerular podo-
cytes, mesangial, as well as several other kidney cell types also express Gb 3
(reviewed in Obrig and Karpman (2012) ). Therefore in addition to the endothe-
lium, other tissues in the kidney may be subject to damage by Stx.
A second clinically important aspect of HUS is the potential development of
neurological symptoms. These can result in epileptic seizures, alterations of con-
sciousness, and paresis ( Nathanson et al., 2010 ). Stx2 is able to induce hindlimb
paralysis when administered to mice by intraperitoneal injection, suggesting that
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