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are sloughed off the apical surface of enterocytes (effacement) and transiently
replaced by elongated microvillus-like processes (
Frankel et al., 1996
)
(
Figure 4.1
C). Effacement of microvilli is followed by actin polymerization
(
Figure 4.1
D) and ultimately the formation of prominent cup-like pedestals
and elongated (up to 10 µm) pseudopod structures (
Rosenshine et al., 1996a,b
).
EPEC utilize these pedestals to attach in very close (intimate) apposition to the
host cell membrane. The pedestal structures are dynamic, being able to change
length, shape, and position over time, and move the attached EPEC along the
host cell surface (
Sanger et al., 1996
). A/E lesions are observed in model EPEC
infections with cultured cells and mucosal explants (
Knutton et al., 1987a,b
;
Hicks et al., 1998
) as well as in intestinal biopsies from EPEC-infected infants
or animals (
Rothbaum et al., 1983
;
Peeters et al., 1988
), but not on formalin-
fixed epithelial cells (
Knutton et al., 1997
). The ability to form A/E lesions is
shared among EPEC, EHEC, and strains of
Escherichia albertii
and
C.rodentium
(
Tzipori et al., 1986
;
Schauer and Falkow, 1993
;
Huys et al., 2003
). All attach-
ing and effacing pathogens carry the LEE, which harbors the genes encoding
intimin,
eae
, the adhesin required for attaching and effacing and the T3SS
(
Elliott et al., 1998
).
Invasion
The ability of EPEC to be internalized by epithelial cells has been noted both
in tissue culture (
Andrade et al., 1989
;
Donnenberg et al., 1989, 1990b
) and
in small intestinal biopsies from EPEC-infected infants (
Fagundes-Neto et al.,
1995
). Several critical EPEC virulence genes, including the
bfp
operon and the
LEE, were first identified via the characterization of mutants lacking the abil-
ity to invade HEp-2 cells (
Donnenberg et al., 1990a,b
). The ability of EPEC to
invade epithelial cells is in marked contrast to their capacity to evade phagocytic
engulfment. Invasion requires the same virulence factors as A/E, therefore, it
has been suggested that invasion is a byproduct of the cytoskeletal rearrange-
ments that occur during the A/E process (
Rosenshine et al., 1996b
). MAP, or
m
itochondrial
a
ssociated
p
rotein, is located immediately upstream of the operon
encoding intimin and Tir. It is targeted to the host cell mitochondrial membrane
where it disrupts the membrane potential. Map also mediates filopodia forma-
tion via Cdc42 (
Kenny and Jepson, 2000
;
Kenny et al., 2002
). This latter func-
tion of MAP has been shown to be involved in EPEC invasion (
Jepson et al.,
2003
). An invasion phenotype has also been associated with other T3S effectors.
EspT causes membrane ruffling and the generation of lamellipodia, via Rac1
and Cdc42 activation, leading to EPEC invasion (
Bulgin et al., 2009
). EspF
and one of its host binding proteins, sorting nexin 9 (SNX9), which regulates
vesicle trafficking and endocytosis, has also been shown to aid in the epithelial
cell invasion of EPEC (
Weflen et al., 2010
). Despite its invasive potential, EPEC
remains classified as an extracellular pathogen; this is likely due to the rarity of
severe inflammation and bacteremia associated with EPEC disease.
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