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expression of Gb
3
receptors, rendering cells more sensitive to Stx challenge
(
van Setten et al., 1997
). TNF-α and IL-1β up-regulate the expression of sev-
eral leukocyte adhesion molecules, such as VCAM-1, E-selectin, and ICAM-
1, potentially enhancing inflammatory damage. LPS and flagellin are believed
to act synergistically with Stx to induce proinflammatory cytokines, and LPS
greatly potentiates Stx in one murine Stx injection model (
Keepers et al., 2006
;
Jandhyala et al., 2010
). In addition, Stx is a potent inducer of proinflammatory
cytokines such as TNF-α, IL-6, and IL-1β (
Harrison et al., 2004
), and depend-
ing on the dose, administration of IL-1β enhances or diminishes Stx toxicity in
mice (
Palermo et al., 2000
;
Lentz et al., 2010
).
IL-1β levels are elevated in HUS patients, raising the possibility that this
cytokine contributes to human disease (
Taneike et al., 2002
). A recent study
unraveled a novel signaling pathway through which EHEC (as well as other
Gram-negative bacteria) induce IL-1β (
Rathinam et al., 2012
). Unlike other
cytokines, the production of IL-1β requires two signals received in a step-
wise fashion. Signal 1, sensed by toll-like receptors (TLRs), such as the LPS-
recognition receptor TLR4, results in the production and accumulation of the
proform of the cytokine, proIL-1β (
Yu and Finlay, 2008
). Signal 2, induced in
response to distinct microbial and endogenous signals in the cytosol, results in
the assembly and activation of inflammasome complexes, which are multipro-
tein platforms containing a pattern recognition receptor (PRR), the adapter pro-
tein ASC, and the autolytic protease caspase-1 (
Schroder and Tschopp, 2010
).
Activated inflammasomes process the constitutively expressed pro-caspase-1
to active caspase-1, which in turn catalyzes the cleavage of proIL-1β into active
IL-1β (
Franchi et al., 2010
;
Schroder and Tschopp, 2010
). Inflammasome-
associated PRRs include Nod-like receptors (NLRs) such as NLRP3, which is
activated by a wide variety of microbial (e.g. pore-forming toxins) or endog-
enous products (
Broz and Monack, 2011
). EHEC infection is sensed by TLR4,
which leads not only to the production of proIL-1β, but also to the activation
of a downstream signaling cascade mediated by an adaptor protein TRIF. The
TLR4-TRIF pathway then induces the production of the proinflammatory type
I interferons, which in turn induce the expression of caspase-11, an inflamma-
tory caspase, that functions in concert with the assembled NLRP3 inflamma-
some to activate caspase-1, leading to IL-1β production (
Rathinam et al., 2012
).
Thus, not only does EHEC proinflammatory signaling likely contribute to tis-
sue damage during EHEC infection, this pathogen has been instrumental in
identifying a TRIF-mediated control point that is critical for regulating innate
immune responses to Gram-negative pathogens.
Whereas the innate immune response may promote disease, an adap-
tive response may provide a degree of protection against STEC infection.
For example, studies in animal models have demonstrated a protective role
for Stx antibodies (
Gupta et al., 2011
). Clinical studies have shown that
STEC patients develop serum antibodies against Stx, LPS, T3SS proteins,
and plasmid-encoded enterohemolysin (
Verweyen et al., 1999
;
Jenkins
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