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signals. Several extracellular factors that regulate LEE expression by targeting some
of the above pathways have been investigated. Growth of EPEC and EHEC in Dul-
becco's modified Eagle's medium (DMEM) at host body temperature (37
°
C), pH
7.0, and physiological osmolarity induces LEE expression, an observation that has
been historically utilized to facilitate investigation of the T3SS (
Kenny and Finlay,
1995
;
Kenny et al., 1997a
). Interestingly, expression of EHEC LEE is regulated by
a quorum-sensing system that recognizes both the bacterial autoinducer AI-3 and
host-derived catecholamines. This inter-kingdom communication involves mul-
tiple two-component systems that positively and negatively regulate both the LEE
and non-LEE-encoded type III effectors (
Kendall and Sperandio, 2007
;
Reading
et al., 2007
;
Hughes and Sperandio, 2008
). Other extracellular factors critical to
LEE expression include iron, sodium bicarbonate, ammonium chloride, calcium,
glucose, and short-chain fatty acids, which are end-products of dietary carbohy-
drate fermentation whose concentrations in the intestine vary depending on the
microbiota and nutrient conditions (
Abe et al., 1997
;
Ide et al., 2003
;
Herold et al.,
2009
;
Delcenserie et al., 2012
).
Although clearly the LEE encodes a central virulence attribute of EHEC
O157:H7, many other loci contribute to the virulence of this bacterium. Several
of the regulatory pathways that control LEE expression also function as regula-
tors of other virulence factors. For example, Ler increases expression of long
polar fimbriae and the secreted protease StcE encoded on the pO157 virulence
plasmid (
Lathem et al., 2002
;
Torres et al., 2007
). The quorum-sensing sys-
tem that recognizes the bacterial autoinducer AI-3 and host catecholamines also
regulates Shiga toxin and flagellae production in a complex manner (
Sperandio
et al., 2002
;
Jeon and Itoh, 2007
).
Disruption of host defense
Immune responses may promote clearance of the bacterium, or could facili-
tate host damage, and an important component of the pathogenesis of EHEC
and other AE pathogens is the ability to disrupt bacterial recognition by the
innate immune system. It has been suggested that EHEC/EPEC infection
blocks phagocytosis, one of the first steps in the development of an antimicro-
bial immune response. T3SS proteins such as EspB, EspF, EspH, and EspJ are
implicated in this antiphagocytic activity of EHEC/EPEC (
Wong et al., 2011
).
EspB binds to the actin binding domains of several myosin family members and
may block the closure of the phagocytic cup (
Diakonova et al., 2002
;
Iizumi
et al., 2007
). EspF also appears to inhibit phagocytosis by binding to actin (
Alto
et al., 2007
). Additionally, EspH blocks phagocytosis by binding and inhibiting
DH-PH domain-containing Rho GTPases, which control cytoskeletal remod-
eling during phagocytosis (
Dong et al., 2010
). In contrast, the mechanism of
EspJ-mediated antiphagocytic activity remains unknown even though it has
been shown to inhibit two phagocytic pathways mediated by FCγR and CR3
(
Marches et al., 2008
).
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