Biology Reference
In-Depth Information
Meningitis-causing
E. coli
K1 strains exploit host cell signaling
molecules for invasion of HBMEC
Several host cell signal transduction pathways have been shown to be involved
in
E. coli
K1 invasion of HBMEC. These include focal adhesion kinase (FAK),
paxillin, phosphatidylinositol 3-kinase (PI3K), Src kinase, signal transducers
and activators of transcription 3 (STAT3), Rho GTPases (RhoA and Rac1),
cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase and cysteinyl leukotri-
enes, vascular endothelial growth factor (VEGF) receptor-1, ezrin, radixin and
moesin (ERM), calmodulin-dependent myosin light-chain kinase, and protein
kinase C (PKC) (
Reddy et al., 2000
;
Kim et al., 2008
;
Kim, 2008, 2010, 2012
;
Teng et al., 2010
;
Zhao et al., 2010
;
Zhu et al., 2010a,b
;
Maruvada and Kim,
2011, 2012
). Despite this substantial list, the underlying host-microbial factors
have been incompletely elucidated.
It is important to note that activations of the above-mentioned host cell sig-
naling molecules occur in response to specific microbial factors of meningitis-
causing
E. coli
K1 and their interactions with HBMEC, and participation of
the same bacterial or host factors does not necessarily lead to activation of the
same host cell signaling molecules. For example, FimH of meningitis-causing
E. coli
has been shown to induce RhoA activation, not FAK activation in HBMEC
(
Khan et al., 2007
). In contrast, FimH of uropathogenic
E. coli
induces FAK
activation in bladder epithelial cells (
Marinez et al., 2000
). A similar concept is
shown with host factors, e.g. gp96 functions as the receptor for
E. coli
OmpA
and
L. monocytogenes
Vip (
Table 10.3
). The OmpA-gp96 interaction resulted in
FAK activation in HBMEC (
Reddy et al., 2000
), but no FAK activation occurred
with the Vip-gp96 interaction in mouse fibroblasts (
Cabanes et al., 2005
).
Our current knowledge on the mechanisms involved with the above-
mentioned host cell signaling molecules for their contribution to HBMEC inva-
sion has been derived from the following two approaches, (a) identification of
the
E. coli
factors participating in specific host cell signaling molecules and
(b) examination of the interrelationship of the host cell signaling molecules
involved in
E. coli
invasion of HBMEC.
Our findings so far demonstrate that OmpA and Ibe proteins of meningi-
tis-causing
E. coli
K1 are involved in FAK and PI3K activations, OmpA and
IbeA in STAT3 and Rac1 activations, FimH and CNF1 in RhoA activation,
OmpA and NlpI in cPLA2 and PKC activations, and CNF1 in ERM activation
(
Figure 10.2
). This information has been useful for elucidating how and why
several bacterial factors contribute to
E. coli
binding to and invasion of HBMEC,
and also whether or not their contributions are redundant. For example, Rac1
activation occurs in response to OmpA or IbeA, and RhoA activation occurs
in response to CNF1 or FimH, while cPLA2 activation occurs in response to
OmpA or NlpI (
Khan et al., 2007
;
Teng et al., 2010
;
Maruvada and Kim, 2011,
2012
). We showed that mutants deleted of OmpA and CNF1, OmpA and FimH,
or FimH and NlpI exhibit significantly greater defects in invasion of HBMEC
compared to individual deletion mutants. In contrast, mutants deleted of OmpA
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