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Avoidance of host responses
Subversion by the T3SS
Like other bacterial pathogens, EPEC has multiple activators of host pattern
recognition receptors including lipopolysaccharide, flagellin, and unmethylated
CpG nucleotides and must contend with the host innate immune response to
establish infection. Histologic examination of EPEC-infected tissue confirms
the induction of an inflammatory response by these bacteria (
Ulshen and Rollo,
1980
;
Higgins et al., 1999a,b
;
Marchès et al., 2000
). However, some reports
noted that the response is rather mild (
Rothbaum et al., 1982
). In cultured epi-
thelial cells, EPEC activates NF-κB which induces the transcription of interleu-
kin 8 (IL-8) (
Figure 4.2
C) (
Savkovic et al., 1996, 1997
). NF-κB functions as a
homo- or heterodimer composed of various subtypes, e.g. RelA (p65), RelB,
c-Rel, p50, and p52. This transcription factor is inactive while sequestered in
the cytoplasm in an IκB-bound complex. Upon stimulation, IκB is phosphory-
lated by IκB kinase (IKK) and targeted for degradation, releasing NF-κB and
allowing the subunits to translocate to the nucleus where they regulate gene
expression (
Karin and Ben-Neriah, 2000
;
Chen, 2005
). EPEC also induces the
activation of the MAP kinase cascade. c-Jun N-terminal kinases (JNKs) are ser-
ine/threonine kinases which belong to the MAP kinase family. Upon activation,
JNKs phosphorylate c-Jun, an AP-1 transcription factor. Despite measurable
activation of these pro-inflammatory cascades, it appears that multiple EPEC
T3S effectors also negatively regulate the host cell response,with T3SS mutants
inducing greater levels of activation (
Sham et al., 2011
). Most of these effectors
are interdependent, multifunctional and redundant (
Dean and Kenny, 2009
).
More details on T3SS effectors can be found in Chapter 15.
The E2348/69 strain contains two
nleH
genes, both of which have been
shown to inhibit pro-inflammatory cytokine expression and promote coloni-
zation (
Royan et al., 2010
). Both NleH1 and NleH2 reduce the abundance of
nuclear ribosomal protein S3 (RPS3), a non-Rel subunit of p65 homodimer and
p65-p50 heterodimer (
Gao et al., 2009
), however, only NleH1 inhibited the
NF-κB activity independent of IκBα phosphorylation and degradation (
Pham
et al., 2012
). NleC and NleD are zinc metalloproteases that specifically cleave
NF-κBp65 and JNK respectively (
Baruch et al., 2011
). This cleavage prevents
transcription of NF-κB- and AP-1-induced genes leading to a marked reduction
in IL-8 secretion (
Yen et al., 2010
;
Baruch et al., 2011
). NleC has also been
found to bind and cleave host acetyltransferase p300, decreasing the inflam-
matory response. NleB and NleE act to inhibit p65 translocation to the nucleus
(
Newton et al., 2010
). NleB inhibits the TNF-α pathway, while NleE is an
S-adenosyl-L-methionine-dependent methyltransferase that prevents the activa-
tion of IKKβ (
Nadler et al., 2010
) by inactivating its kinase activity (
Zhang
et al., 2012
). Recently, Tir has been shown to inhibit NF-κB activation by induc-
ing TNF-α receptor associated factor (TRAF) protein degradation (
Ruchaud-
Sparagano et al., 2011
).
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