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alleles having 97% sequence homology with one another, and the beta alleles
are more divergent with 89% homology. The sequence diversity is concen-
trated at amino acids 137-155 in the C-terminal regions of bundlin, many of
which are found on the surface of bundlin monomers polymerized into BFP
(
Ramboarina et al., 2005
). While it is unknown whether anti-bundlin antibod-
ies confer protective immunity, sera from volunteers rechallenged with an
alpha bundlin strain of EPEC showed increases in response that were type-
specific (
Fernandes et al., 2007
). Little research is available on the immune
responses to other
E. coli
T4P.
THERAPEUTICS AND VACCINE PROSPECTS
As mentioned above, vaccine development for
E. coli
human pathogens is com-
plicated by the lack of a valid model for study. Mouse models are commonly
used for studying
E. coli
T3S homologs in
Citrobacter rodentium
(
Frankel
et al., 1996
;
Deng et al., 2003
;
Kelly et al., 2006
), and a rabbit model for rab-
bit EPEC, has also been utilized (
Peeters et al., 1988
;
Milon et al., 1992
), as
have porcine (
Girard et al., 2005
) and bovine in vitro cell models (
Moxley and
Francis, 1986
). A mouse model for EPEC was previously proposed (
Savkovic
et al., 2005
) but the adherence in both a mouse cell line and in vivo was very
low, and the model has not been duplicated (
Guttman et al., 2006
). In the above
instances, factors other than BFP are used by these pathogens for initial attach-
ment to intestinal epithelial cells. These differences preclude using an existing
animal model to study potential BFP vaccine candidates. Natural infections with
BFP-expressing EPEC in dogs, birds and non-human primates hint of potential
vaccine models yet to be developed (
Beaudry et al., 1996
;
Schremmer et al.,
1999
;
Carvalho et al., 2003
).
ANTIVIRULENCE DRUGS
Most currently available antibiotics inhibit general bacterial growth or cause
bacterial cell death, resulting in strong selective pressure for the emergence of
antibiotic resistance. A focus on interrupting bacterial virulence may decrease
this selective pressure. Due to the conservation of components and mechanism
of action between T2S and T4P, drug design to target specific components of
these systems could be advantageous. Both machines require tightly coordi-
nated protein-protein interactions suggesting targets for chemotherapy. Most of
the proteins in these systems have no human homologs, decreasing the likeli-
hood of adverse effects (
Peabody et al., 2003
). Several studies have attempted
to identify antivirulence drugs against T2S and T4P systems (
Baron, 2010
).
Felise et al. identified a compound that inhibited both T2S and T3S in vitro and
decreased secretion when cultured with eukaryotic cells (
Felise et al., 2008
).
Further studies are needed to determine whether these advances will translate
to clinical benefit.
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