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EHEC/EPEC further disrupts mounting of an effective proinflammatory
response by interfering with innate immune signaling pathways. A common tar-
get in the host for this purpose is the nuclear factor kappa B (NF-κB), a key pro-
teinin expression, and production of proinflammatory cytokines. Normally, the
NF-κB-inhibitory protein IκB sequesters NF-κB in an inactive state, and upon
activation of pattern recognition receptors such as TLRs by pathogen-associated
molecular patterns (PAMPs), active NF-κB is released from IκB and translo-
cates from the cytosol to the nucleus to activate transcription of target genes,
such as those encoding proinflammatory cytokines and chemokines (
Kawai and
Akira, 2007
). These proinflammatory mediators potentially promote clearance
of the infection.
Some of the most detailed studies addressing disruption of inflammatory
signaling in the host cell involve the action of non-LEE encoded (Nle) type-III-
secreted effectors such as NleE, NleB, NleC, NleD, and NleH. Partly because
type III translocation by
in vitro
cultivated EPEC is more efficient than that
by EHEC, work on type III effectors shared by the two pathogens has been
performed largely in EPEC. Given the high sequence homology of EPEC and
EHEC (and
C. rodentium
) effector alleles, it seems likely that the mechanisms
of action are conserved among all the AE pathogens (see also
Table 5.3
). NleE
appears to inhibit TNFα-induced NF-κB activation by inhibiting its nuclear
translocation (
Zurawski et al., 2008
;
Newton et al., 2010
;
Vossenkamper et al.,
2010
). Recent studies indicate that NleE modifies host ubiquitin chain sen-
sory proteins, TAB2/3, to disrupt host NF-κB signaling (
Zhang et al., 2012
).
NleE also prevents degradation of IκB by inhibiting activation of IKKbeta
resulting in further NF-κB suppression (
Nadler et al., 2010
). NleB, has been
shown to enhance this particular activity of NleE (
Nadler et al., 2010
). Further-
more, NleC and NleD have been shown to cleave the p65 subunit of NF-κB
and c-Jun N-terminal kinase (JNK), preventing inflammatory responses (
Ye n
et al., 2010
). Additionally, EHEC homologs NleH1 and NleH2 also can bind
to NF-κB subunit RPS3 (
Wan et al., 2011
). All these findings demonstrate
that EHEC/EPEC has evolved a strategy to interfere with the induction of a
proinflammatory response by simultaneously blocking multiple steps in the
inflammatory signaling cascade through the concerted activity of several T3SS
effector proteins.
Host damage
During infection, AE pathogens attach to the luminal surfaces of the host intes-
tinal epithelia where they efface localized regions of microvilli, form actin ped-
estals, and translocate effector proteins into the host cell. Many of these effector
proteins have been shown to subvert various cellular processes and dramatically
alter the function of intestinal cells, influencing colonization and likely contrib-
uting significantly to the development of diarrhea (for review see
Frankel et al.
(1998a)
and
Wong et al. (2011)
).
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