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In-Depth Information
Stx is directly responsible for some aspects of neurologic disease in EHEC infec-
tion (
Obata et al., 2008
). Consistent with this notion, Stx2 was shown
in vivo
to act
on Gb
3
-expressing neurons, and treatment of murine brain slices
ex vivo
resulted
in increased Ca
2+
transients by astrocytes in response to electric field stimulation.
Complement activation contributes to the vascular damage associated with
over 50% of cases of 'atypical' HUS, i.e. HUS not associated with diarrheal
(e.g. STEC) disease (
Besbas et al., 2006
;
Loirat and Fremeaux-Bacchi, 2011
)
and may also play a role in Shiga toxin- (diarrhea-)associated HUS ('D+HUS')
(reviewed in
Noris et al. (2012)
). C3 deposits on human microvascular endo-
thelial cells that have been treated with Stx1 and perfused with human serum
(
Morigi et al., 2011
). When these cells are perfused with whole blood, Stx1
pretreatment is associated with an increase in cell surface thrombi, an event
that is blocked by the complement inhibitor sCR1. Treatment of human serum
with Stx2 results in the formation of sC5b-9, indicating that Stx2 is also able to
activate complement (
Orth et al., 2009
). A complement component 3a receptor
antagonist diminishes glomerular fibrin deposition and platelet clumps when
administered to mice prior to challenge with Stx2 and LPS (
Morigi et al., 2011
)
and mice deficient in factor B of the alternative complement pathway did not
suffer renal impairment upon Stx2/LPS challenge. Children with documented
or suspected D+HUS had perturbations in serum levels of complement com-
ponents, e.g. decreased levels of C3 or increased levels of C3b, Ba, Bb, and/or
sC5b-9 (
Cameron and Vick, 1973
;
Kaplan et al., 1973
;
Monnens et al., 1974,
1980
;
Robson et al., 1992
;
Thurman et al., 2009
;
Lapeyraque et al., 2011
). One
study demonstrated that increased plasma levels of C3a and sC5b-9 during the
onset of D+HUS subsequently normalized upon recovery (
Stahl et al., 2011
).
Thus, although the signaling mechanism(s) by which Stxs promote complement
activation has not been elucidated, these data suggest that complement activation
is associated with D+HUS.
As mentioned above, Stx can induce pro-inflammatory signaling via the
RSR, PI3/AKT/mTOR pathways, and apoptotic signaling via the RSR and
UPR pathways
in vitro
. HUS patients manifest elevated urinary and/or serum
levels of MCP-1, IL-6, IL-8, and TNF-α (
Karpman et al., 1995
;
Inward et al.,
1997
;
van Setten et al., 1998
). PMN counts are elevated during HUS, and
together with increased IL-8 levels, are prognostic indicators of severe dis-
ease (
Fitzpatrick et al., 1992
;
Robson et al., 1992
;
Fernandez et al., 2007
).
Furthermore, apoptotic glomerular and renal tubular cells are present in the
kidneys of HUS patients (
Karpman et al., 1998
;
Kaneko et al., 2001
;
Te
Loo et al., 2001a
). Thus, it is reasonable to hypothesize that the RSR, PI3/
AKT/mTOR, and UPR signaling pathways contribute at least in part to the
pathology associated with HUS. However, future studies are required to bet-
ter characterize the mechanism by which HUS develops, and whether other
bacterial factors such as LPS, which is an integral component in one murine
Stx model (
Keepers et al., 2006
), act in concert with Stx to promote severe
disease.
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