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Despite being an inhibitor of protein synthesis,
in vitro
studies have dem-
onstrated that intoxication by Shiga toxin results in a paradoxical increase in
cytokine expression (
Sakiri et al., 1998
;
Thorpe et al., 1999
;
Foster et al., 2000
;
Thorpe et al., 2001
). Shiga toxins have been shown to regulate cytokine expres-
sion through the ribotoxic stress response (RSR) and the phosphatidylinositol
3-kinase/Akt/mammalian target of rapamycin signaling (PI3/AKT/mTOR)
pathway (
Colpoys et al., 2005
;
Cherla et al., 2006, 2009
;
Jandhyala et al., 2008,
2012
). Cytokines induced by Shiga toxins include interleukin-8 (IL-8), tumor
necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) (
van
Setten et al., 1996
;
Thorpe et al., 1999
;
Cherla et al., 2006, 2009
;
Jandhyala
et al., 2008
). In addition to promoting cytokine expression,
in vitro
studies have
also demonstrated that Shiga toxins induce apoptotic signaling via the RSR and
the unfolded protein response (UPR) (
Smith et al., 2003
;
Lee et al., 2008b
).
As STEC are enteric pathogens and generally non-invasive, in order to cause
systemic disease such as HUS, Shiga toxins have to pass from the intestinal
lumen, where they are produced, to the systemic circulation, where the toxin can
access the microvasculature of the kidney and the central nervous system. Intesti-
nal infection of mice with a genetically engineered Stx-producing
C. rodentium
,
which like EHEC generates AE lesions on intestinal epithelial cells, suggests that
colonization of the mucosal surface may promote systemic intoxication (E. Mal-
lick and J. Leong, unpublished observations).
In vitro
data have suggested that
Shiga toxins may cross the epithelial barrier via a transcellular route that does not
result in the death of the enterocyte (
Acheson et al., 1996
;
Philpott et al., 1997
;
Malyukova et al., 2009
). Alternatively, Shiga toxins may enter the systemic cir-
culation via a paracellular route, consistent with
in vitro
studies suggesting that
luminal infiltration of polymorphonuclear leukocytes (PMNs) may promote the
basolateral uptake of Stxs (
Hurley et al., 2001
). Indeed, histological analyses of
patients with STEC-associated hemorrhagic colitis show large infiltrates of neu-
trophils in the lamina propria and crypts of the large intestine (
Griffin et al., 1990
).
There is currently a lack of consensus as to the role Shiga toxins play in
promoting intestinal damage. Murine infection with Stx-producing
C. rodentium
results in toxin-dependent damage to the intestinal epithelium (
Mallick et al.,
2012b
) although it has not been determined whether Stx damages the epithelium
directly or indirectly, e.g. by compromising blood supply to the mucosa. Several
studies have suggested that, with the exception of the enteric endothelium and
Paneth cells, the human intestine is devoid of the Stx receptor Gb
3
(
Holgersson
et al., 1991
;
Berin et al., 2002
;
Schuller et al., 2004, 2007
;
Miyamoto et al., 2006
).
In contrast, Zumbrum et al. suggested that human colonic epithelium expresses
the Stx receptor Gb
3
, albeit at low levels (
Zumbrun et al., 2010
). Whether or
not Gb
3
is expressed in the human colonic epithelium, Stx has been detected in
epithelium from the illeocecal valves of patients infected with STEC, suggesting
that Stx has the potential to enter these cells (
Malyukova et al., 2009
). In addi-
tion, Stx was found in expelled cells in the lumen, although whether these cells
were damaged directly by Stx was not determined. It has been proposed that
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