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Subversion of innate immunity
In mammals a complex set of signaling networks initiate both innate and adap-
tive immune responses against bacterial pathogens. Pathogens have therefore
evolved sophisticated mechanisms to subvert these signaling networks in order
to circumvent host innate immune responses.
EPEC infection in vivo results in intestinal tissue damage, neutrophil infil-
tration of the infected mucosa and damage of the gut epithelium (
Savkovic
et al., 1996
;
Chakravortty and Kumar, 1999
;
Michail et al., 2003
). This pathol-
ogy has been linked to the inflammatory responses mounted by the cells of the
infected tissues. EPEC and EHEC interaction with the gut mucosa results in
the stimulation of pattern recognition receptors (PRRs), such as toll-like recep-
tors (TLRs), that recognize specific pathogen-associated molecular patterns
(PAMPs), including flagellin and lipopolysaccharide (LPS) (
Khan et al., 2006
;
Schuller et al., 2009
). TLRs initiate signaling pathways downstream of these
receptors ultimately converging on a set of transcriptional activators including
interferon-regulatory factors (IRFs), nuclear factor-κB (NF-κB), and mitogen-
activated protein kinases (MAPKs) resulting in the expression and secretion of
pro-inflammatory chemokines and cytokines such as interleukin 8 (IL-8), IL-6,
IL-12, and tumor necrosis factor α (TNFα).
The pathway best described in the case of EPEC infection is the NF-κB
pathway. The NF-κB family comprises five proteins that can form homo- and/
or heterodimeric complexes: RelA (p65), RelB, c-Rel, p50 (NF-κB1), and p52
(NF-κB2), but the most abundant form in mammalian tissues is the dimer p50/
p65 (
Li and Verma, 2002
). Under non-stimulating conditions, NF-κB is kept
inactive in the cytoplasm through its association with inhibitory proteins (IκBs),
this interaction masks the nuclear localization signal (NLS) of p65 thus pre-
venting nuclear translocation. Molecular mechanisms that lead to NF-κB acti-
vation have been studied intensively. Briefly, ligand-bound TLRs recruit the
adaptor protein MyD88, which in turn recruits the IL-1R-associated kinases 1
(IRAK1) and 4 (IRAK4), leading to their sequential autophosphorylation and
activation (
Silverman and Maniatis, 2001
). Phosphorylated IRAK1 then associ-
ates with TNF receptor-associated factor 6 (TRAF6). This association activates
the E3 ubiquitin ligase function of TRAF6, which, with the UBC13/UEV1 E2
ubiquitin-conjugating complex, catalyzes the synthesis of Lys-63-linked poly-
ubiquitin chains (
Deng et al., 2000
). These ubiquitin chains serve as a scaffold
to recruit both the transforming-growth-factor-β-activated kinase 1 (TAK1) and
IκB kinase complexes (IKK) through their respective ubiquitin-binding sub-
units, TAK-binding protein 2 and 3 (TAB2/3) and NF-κB essential modulator
(NEMO) (
Kanayama et al., 2004
;
Ea et al., 2006
;
Wu et al., 2006
). As a result
of their proximity, TAK1 can phosphorylate the IKK-β subunit of IKK, which
then phosphorylates IκBα. Release of NF-κB dimers occurs after phosphoryla-
tion of IκB which allows the ubiquitination by SCFβTrCP complex and subse-
quent proteasomal degradation of IκBα, allowing NF-κB translocation into the
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