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uptake and RhoA activation in HBMEC were inhibited by LRP antisense oli-
godeoxynucleotides, whereas they were increased in LRP-overexpressing cells
(
Chung et al., 2003
). These findings support the concept that the expression
level of host cell receptor(s) dictates the fate of
E. coli
interaction with HBMEC
in a bacterial ligand-dependent manner. In addition, pharmacological inhibition
and gene deletion of host cell signaling molecules (e.g. cPLA2) involved in
E. coli
invasion of HBMEC was efficient in preventing
E. coli
penetration into
the brain (
Zhu et al., 2010a,b
). These findings suggest that pharmacological
inhibition of the HBMEC receptors that interact with
E. coli
factors and host
cell signaling molecules contributing to
E. coli
invasion of HBMEC might be a
novel strategy for prevention of
E. coli
meningitis.
The feasibility of this novel strategy was shown by our demonstration
that pharmacological inhibition of the host cell receptor (e.g. LRP) and host
cell signaling molecules (e.g. cysteinyl leukotrienes) involved in
E. coli
invasion of HBMEC was efficient in preventing
E. coli
penetration into the
brain (
Kim, 2010, 2012
;
Zhu et al., 2010a,b
). Additional studies are needed
to elucidate the microbial-host factors that contribute to
E. coli
invasion of
HBMEC and also can serve as novel targets for prevention and therapy of
E. coli
meningitis.
An additional novel strategy for prevention and therapy of
E. coli
meningitis
is to modulate the interaction with the blood-brain barrier of the microbial factors
contributing to HBMEC binding and invasion by affecting their expression and/
or secretion. For example, CNF1 is a key factor contributing to
E. coli
invasion of
HBMEC and penetration into the brain via the interaction with its receptor (LRP)
on HBMEC (
Khan et al., 2002
;
Chung et al., 2003
). CNF1, however, is a cytoplas-
mic protein and execution of its contribution to
E. coli
invasion of the blood-brain
barrier requires its secretion from the bacterial cytoplasm. No signal peptide is
found in the CNF1 sequence. CNF1 secretion is, therefore, a strategy utilized by
meningitis-causing
E. coli
to invade the blood-brain barrier. It, however, remains
unclear how CNF1 secretion occurs across the bacterial inner membrane and
outer membrane as well as into outer membrane vesicles. We have shown that
ferredoxin is involved in CNF1 secretion across the bacterial inner membrane and
YgfZ is involved in CNF1 secretion into outer membrane vesicles (
Yu and Kim,
2010, 2012
). Elucidation of the mechanisms involved in CNF1 secretion will,
therefore, enhance our knowledge on the pathogenesis of
E. coli
meningitis and
also help in developing a novel strategy targeting CNF1 secretion in prevention
of
E. coli
meningitis. Taken together, these findings suggest that modulation of
bacterial secretion systems (CNF1 secretion, type III secretion, type VI secretion)
is likely to represent a novel target for prevention of
E. coli
meningitis.
THE BASIS FOR NEUROTROPISM IN
E. COLI
MENINGITIS
E. coli
strains possessing the K1 capsular polysaccharide are predominant
(approximately 80%) among isolates from neonatal
E. coli
meningitis and
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