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by use of both the in vitro and in vivo blood-brain barrier models (
Huang et al.,
1995, 1999
;
Wang et al., 1999
).
Exogenous recombinant Ibe proteins were shown to inhibit meningitis-
causing
E. coli
K1 invasion of HBMEC (
Huang et al., 1995
), suggesting that
Ibe proteins contribute to HBMEC invasion by ligand-receptor interactions. This
concept was supported by the demonstration of a HBMEC surface protein inter-
active with IbeA, and a polyclonal antibody raised against this receptor protein
inhibited
E. coli
K1 invasion of HBMEC (
Kim, 2001
). The gene,
ibeA
, was shown
to be prevalent in meningitis-causing
E. coli
K1 of phylogenetic B2 group (
John-
son et al., 2002
;
Bonacorsi et al., 2003
), while
ibeB
and
ibeC
were found to have
homologs in non-meningitis isolates of
E. coli
. It remains unclear whether the
ibeB
and
ibeC
homologs from non-meningitis isolates will exhibit the HBMEC
invasion phenotype similar to that of meningitis-causing
E. coli
K1 strains. The
mechanisms involved with IbeA, IbeB, and IbeC in their contributions to
E. coli
K1 invasion of HBMEC, however, appear to be similar and their contributions to
HBMEC invasion are likely to be redundant. This is shown by the demonstration
that HBMEC invasion frequencies did not differ significantly between mutants
deleted of
ibeA
,
ibeB
, and
ibeC
versus mutants deleted of single or double genes
(
Kim, 2002
). Additional studies are needed to elucidate the mechanisms involved
with IbeA, IbeB, and IbeC for their contribution to
E. coli
meningitis.
CNF1
CNF1 is a bacterial virulence factor associated with extraintestinal pathogenic
E. coli
strains causing urinary tract infection and meningitis (
Bouquet, 2001
).
CNF1 is an AB-type toxin, composed of the N-terminal cell binding domain and
the C-terminal catalytic domain possessing a deaminase activity through the
site-specific deamination of a Gln residue to Glu (
Flatau et al., 1997
;
Schmidt
et al., 1997
). CNF1 has been shown to activate RhoGTPases such as RhoA and
induce uptake of latex beads, bacteria, and apoptotic bodies into non-profes-
sional phagocytes such as epithelial and endothelial cells by macropinocytosis
(
Fabbri et al., 2002
).
CNF1 contributes to
E. coli
K1 invasion of HBMEC in vitro and traversal of
the blood-brain barrier in vivo, and these in vitro and in vivo effects of CNF1
are dependent upon RhoA activation (
Khan et al., 2002
). These conclusions
were shown by (a) significantly decreased invasion and RhoA activation with
the CNF1 deletion mutant compared to the parent strain in HBMEC and (b)
restoration of the CNF1 mutant's invasion frequency to the level of the parent
strain in HBMEC expressing constitutively active RhoA.
CNF1 has been suggested to be internalized via receptor-mediated endo-
cytosis upon binding to a cell surface receptor (
Bouquet, 2001
). We have
identified the HBMEC receptor for CNF1 by yeast two-hybrid screening
of the HBMEC cDNA library using the N-terminal cell-binding domain of
CNF1 as bait (
Chung et al., 2003
). This receptor, 37-kDa laminin receptor
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