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actin assembly. In fact, a mutant with this phenotype, i.e. an EHEC
espF
U
/
tccP
mutant, is defective for colonization of infant rabbits at late time points and
forms unusually small bacterial aggregates in intestines of gnotobiotic piglets
(
Ritchie et al., 2008
). Additionally,
C. rodentium
mutants similarly specifically
defective in generating actin pedestals have diminished colonization ability dur-
ing coinfection with wild-type bacteria (
Crepin et al., 2010
), or were found
to be deficient in colonizing the colonic mucosa and causing lethal disease in
an Stx-producing
C. rodentium
model (E. Mallick, unpublished observation).
These findings indicate that pedestal formation by EHEC promotes coloniza-
tion and stx-mediated disease.
Regulation of gene expression
Expression of major EHEC virulence factor genes, such as
stx
, the large pO157
plasmid, and the LEE, is regulated by multiple genes and environmental signals.
(A detailed description of the highly complex pathways of EHEC regulation
is beyond the scope of this chapter and readers are referred to recent reviews
(
Mellies et al., 2007
;
Croxen and Finlay, 2010
)). Regulation of the LEE, which
is comprised of 41 open reading frames arranged in five major polycistronic
operons,
LEE1
through
LEE5
, has been the subject of considerable investiga-
tion. An important element of LEE regulation involves the global nucleopro-
tein-like regulator H-NS, which acts as a major suppressor of LEE expression
(
Bustamante et al., 2001
). Ler, the major
LEE
-encoded regulator, is central to the
control of LEE expression, and disrupts H-NS-mediated silencing of LEE (
Mel-
lies et al., 2007
), leading to increased transcription of operons
LEE2
through
LEE5
. The additional LEE-encoded regulators include GrlA (global regulator of
LEE activator) and GrlR (global regulator of LEE repressor). GrlA binds to Ler
promoter and acts as an H-NS antagonist thereby promoting the expression of
Ler (
Jimenez et al., 2010
). GrlR interacts with GrlA, interfering with the GrlA-
mediated induction of Ler leading to an inhibition of LEE expression (
Iyoda
et al., 2006
).
LEE expression is also controlled by regulators encoded elsewhere on the
EHEC genome. Some of these, such as Pch (
Iyoda and Watanabe, 2004
), IHF
(
Yona-Nadler et al., 2003
), RcsCDB and GrvA (
Tobe et al., 2005
) induce LEE
expression by increasing Ler production. Negative regulators of LEE, such as
GadE, GadF (
Tatsuno et al., 2003
;
Kailasan Vanaja et al., 2009
), EtrA and EivF
(two regulatory proteins of
E. coli
type III secretion system 2, ETT2) (
Zhang
et al., 2004
), Hha (
Sharma and Zuerner, 2004
), CadA (
Vazquez-Juarez et al.,
2008
), and SdiA (
Kanamaru et al., 2000
;
Sharma et al., 2010
) regulate LEE
expression mainly by inhibiting Ler. Finally, the sRNA chaperone Hfq regulates
the LEE in a strain-specific manner, indicating that the LEE is subject to com-
plex regulation by sRNA (
Hansen and Kaper, 2009
).
During intestinal infection, EHEC is exposed to extracellular factors, such as
EHEC-secreted components, products of the existing microbiota, and host-derived
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