Biology Reference
In-Depth Information
Rac1, as shown by blockade of Rac1 activation in HBMEC expressing domi-
nant-negative STAT3 (
Maruvada and Kim, 2012
). Also, cPLA2 and PKC are
involved in meningitis-causing
E. coli
K1 invasion of HBMEV, but cPLA2 is
upstream of PKC, as shown by the demonstration that inhibition of cPLA2 pre-
vents PKC activation in response to meningitis-causing E.
coli
K1 in HBMEC
(
Zhu et al., 2010a
).
Despite the above information, it remains incompletely understood why sev-
eral microbial factors contribute to HBMEC binding and invasion. It remains to
be determined whether complete abolition of such phenotypes requires deletion
of all the non-redundant bacterial factors contributing to HBMEC binding and
invasion.
It should also be noted that host cell actin cytoskeleton rearrangements are
required for HBMEC invasion by meningitis-causing bacteria such as
E. coli
,
group B
Streptococcus
and
L. monocytogenes
, as shown by inhibition of their
invasion into HBMEC by cytochalasin D (
Nizet, 1997
;
Greiffenberg et al., 1998
;
Nemani et al., 1999
), but the host cell signaling mechanisms involved in actin
cytoskeleton rearrangements and HBMEC invasion differ between meningitis-
causing bacteria. For example,
E. coli
K1 invasion of HBMEC depends on acti-
vations of FAK, Src, and cPLA2. In contrast, group B
Streptococcus
invasion
of HBMEC is independent of Src and
L. monocytogenes
invasion of HBMEC is
independent of FAK and cPLA2 activation (
Das et al., 2001
;
Kim, 2001
).
E. coli
traversal of the blood-brain barrier as live bacteria
Another crucial factor for the development of meningitis is the ability of menin-
gitis-causing bacteria to cross the blood-brain barrier as live bacteria.
E. coli
K1
has been shown to traverse the blood-brain barrier as live bacteria without alter-
ing the integrity of the HBMEC monolayer and without affecting the blood-
brain barrier permeability as well as without accompanying host inflammatory
cells (
Kim et al., 1992, 1997
;
Stins et al., 2001
).
As indicated above, internalized
E. coli
are located within membrane-bound
vacuoles of HBMEC and transmigrate the HBMEC monolayer (
Figure 10.1
).
We showed that HBMEC have the complete intracellular trafficking machin-
ery required to deliver the microbe-containing vacuoles to cathepsin D-con-
taining components (i.e. lysosomes) (
Kim et al., 2003
). For example, vacuoles
containing
E. coli
K1 capsule deletion mutant interact sequentially with early
endosomal marker proteins (e.g. early endosomal auto-antigen 1 and transferrin
receptor) and late endosome and late endosome/lysosomal markers (e.g. Rab7
and lysosome-associated membrane proteins, respectively), and allow lyso-
somal fusion with subsequent degradation inside vacuoles. In contrast, vacuoles
containing
E. coli
K1 encapsulated strain obtained early and late endosomes
but without fusion with lysosomes, thereby allowing
E. coli
K1 to cross the
blood-brain barrier as live bacteria (
Kim et al., 2003
), indicating that
E. coli
K1 capsule modulates intracellular trafficking to avoid lysosomal fusion in
HBMEC (
Figure 10.3
).
Search WWH ::
Custom Search