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In-Depth Information
Molecular pathogenesis
Adherence and invasion
AIEC's ability to adhere to epithelial cells is mediated primarily by the type
I pili, which interact with the host receptor CEACAM6. This receptor is
abnormally over-expressed by the ileal epithelium in CD patients (
Carvalho
et al., 2009
). AIEC-induced colitis in transgenic mice depends on both bacte-
rial type I pili expression and human CEACAM6 expression in the intestine
(
Carvalho et al., 2009
). The earliest lesions of CD are microscopic erosions
of the follicle-associated epithelia lining the Peyer's patches (PPs). AIEC is
able to adhere to the specialized M cells in PPs through the type I pili and the
long polar fimbriae (Lpf) (
Chassaing et al., 2011
), favoring its translocation
through M cells, which may explain the detection of AIEC in the lamina pro-
pria of CD patients. The invasion properties of AIEC are associated with the
extrusion of microvillar extensions from the host cell membrane that engulf
the bacteria, resembling macropinocytosis induced by other intracellular
pathogenic bacteria (
Darfeuille-Michaud, 2002
). However, this mechanism
for AIEC depends on both actin microfilaments and microtubules (
Darfeuille-
Michaud, 2002
), while invasion for other pathogens depends exclusively on
actin cytoskeleton rearrangements. Type I pili have been involved in the inva-
sion of intestinal epithelial cells, and mutants in the
fimI
and
fimF
gene prod-
ucts, involved in the type I pili biogenesis, still adhere to IECs but their ability
to induce membrane elongations at the site of contact is impaired (
Boudeau
et al., 2001
). Further, outer membrane vesicles (OMV) containing biologi-
cally active proteins function as an efficient secretion pathway and are also
important for AIEC invasion. For example, an
yfgL
mutant, showing reduced
release of OMV, displays a diminished ability to invade intestinal cells (
Rol-
hion et al., 2005
). The endoplasmic reticulum stress protein Gp6 is also over-
expressed in the ileum of CD patients; it co-localizes with CEACAM6 and
functions as a receptor for the bacterial OmpA located on the surface of OMV
(
Rolhion et al., 2010
). Although AIEC-specific content in the OMV is neces-
sary for promoting invasion (
Rolhion et al., 2010
), the nature of the effector
proteins delivered by OMV is still unknown.
Regulation
Compared to other
E. coli
pathotypes, little is known about the mechanisms
regulating expression of virulence factors in AIEC. The expression of the
fim
operon is regulated by the orientation of an invertible DNA element that
includes the
fim
promoter (the
fim
ON and OFF switch). The orientation of this
invertible element is determined by the activity of the FimB and FimE recombi-
nases (
Klemm, 1986
). In AIEC,
fim
is repressed in mutants defective in flagella
assembly, generally as a result of a preferential switch towards the OFF state of
the invertible element (
Barnich et al., 2003, 2004
;
Claret et al., 2007
). A reduc-
tion in the transcription of the
fimB
and
fimE
genes, together with a reduction
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