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The best-characterized adhesin of EHEC, and an absolutely essential viru-
lence factor, is the ∼94-kDa outer-membrane protein intimin, encoded by the
eae
gene (
Jerse et al., 1990
;
Donnenberg and Kaper, 1991
;
Beebakhee et al.,
1992
;
Yu and Kaper, 1992
). Intimin is an integral outer membrane protein with
three domains: a flexible N-terminal region thought to be located in the peri-
plasm, a central region that forms a β-barrel in the outer membrane, and a sur-
face-exposed C-terminal receptor-binding domain (
Ross and Miller, 2007
;
Yi
et al., 2010
). The latter domain exhibits considerable allelic variation (
Frankel
et al., 1994
), with at least ten different intimin subtypes (
Adu-Bobie et al., 1998
;
Oswald et al., 2000
).
Intimin was first identified by its essential role in the formation of the char-
acteristic attaching and effacing (AE) lesions on the surface of intestinal epi-
thelial cells (
Jerse et al., 1990
;
Donnenberg and Kaper, 1991
). AE lesions are
characterized by effacement of microvilli, intimate bacterial attachment to epi-
thelial cells, and the formation of localized actin assembly, i.e. filamentous (F-)
actin 'pedestals', beneath bound bacteria (
Staley et al., 1969
;
Ulshen and Rollo,
1980
;
Moon et al., 1983
). Intimin promotes AE lesion formation by binding to
Tir (translocated intimin receptor), a type III-secreted effector that localizes in
the host plasma membrane after translocation into mammalian cells (see below)
(
Kenny et al., 1997b
;
Hartland et al., 1999
). Thus, intimin is required for tight
attachment to cultured cells, as well as for colonization and virulence during
mammalian infection (
Donnenberg et al., 1993b
;
McKee et al., 1995
;
Tzipori
et al., 1995
;
Dean-Nystrom et al., 1998
).
Intimin may possess Tir-independent functions as well. Intimin of the
related EPEC has been shown to contribute to the disruption of epithelial
barrier function of polarized monolayers in a Tir-independent manner (
Dean
and Kenny, 2004
), a function that may be related to Tir-independent host
cell attachment. Indeed, intimin promotes binding to cultured cells in the
absence of Tir, albeit with much lower efficiency than in the presence of
Tir binding. (
Frankel et al., 1994
;
McKee and O'Brien, 1995
;
Frankel et al.,
1998a, b
;
Hartland et al., 1999
). Several host cell receptors, including β1-
chain integrins (
Frankel et al., 1996
;
Sinclair et al., 2006
) and nucleolin
(
Sinclair and O'Brien, 2002
;
Sinclair et al., 2006
) have been shown to have
the capacity to bind intimin. Interestingly, Stx2 (see below) has been shown
to enhance adherence of EHEC to intestinal epithelial cells and intestinal
colonization in mice by increasing the surface localization of nucleolin
(
Robinson et al., 2006
;
Liu et al., 2010
). Whereas all alleles of intimin bind
to Tir, alleles differ in promoting epithelial colonization in some experimen-
tal models, consistent with a Tir-independent colonization function (
Tzipori
et al., 1995
;
Phillips and Frankel, 2000
;
Fitzhenry et al., 2002
;
Girard et al.,
2005
;
Mundy et al., 2007
). Finally, intimin of the murine pathogen Citro-
bacter rodentium, which also generates AE lesions (see below), plays a Tir-
independent role in colonization of streptomycin-pretreated mice (
Mallick
et al., 2012a
).
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