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Virulence gene regulation
Overcoming multiple host barriers often requires coordinated expression of
multiple, sometimes unlinked, genes encoding complex virulence systems such
as the
Shigella
T3SS. Furthermore, it is beneficial to the invading pathogen to
express virulence factors required for access to and fitness in host tissues only
when these tissues are encountered. Like other bacterial pathogens,
Shigella
and EIEC have evolved regulatory cascades that respond to temperature as an
environmental stimulus. This signal coordinates virulence gene expression dur-
ing transit from the environment into the human gut. Temperature regulation of
Shigella
and EIEC virulence genes operates at the level of gene transcription.
Expression of the
ipa, mxi,
and
spa
operons is induced 50 to 100-fold when
the bacteria are shifted from 30°C to 37°C (
Hromockyj and Maurelli, 1989
).
Genes governing this thermal regulation include
virR/hns
, located on the chro-
mosome, and two virulence plasmid genes,
virF
and
virB
. The histone-like pro-
tein (H-NS), encoded by
virR/hns
, is a repressor of virulence gene expression.
In
hns
mutants, the
ipa, mxi,
and
spa
operons are expressed at the normally
repressive temperature (30°C) (
Maurelli and Sansonetti, 1988
). The
virR/hns
locus is allelic with regulatory loci in other enteric bacteria and, like
virR/hns
,
these alleles act as repressors of their respective regulons. The ability of H-NS
to bind curved DNA, which is commonly found in promoter regions, accounts
for its involvement in gene regulation in response to diverse environmental
stimuli such as osmolarity, pH and temperature (
Dorman, 2004
). H-NS binds
to the
virF
and
virB
promoters, as well as to promoters controlled by VirB, and
prevents transcription of these genes at 30 °C (
Belboin and Dorman, 2003
).
The product of the
virF
locus is a key element in temperature regulation of
the
Shigella
virulence regulon. A helix-turn-helix motif in the carboxyl terminal
portion of VirF is characteristic of members of the AraC family of transcrip-
tional activators. VirF binds to sequences upstream of
virB
, which is consistent
with its predicted role as a DNA-binding protein (
Tobe et al., 1993
). Transcrip-
tion of
virB
is dependent on growth temperature and VirF (
Adler et al., 1989
;
Tobe et al., 1991, 1993
). VirB resembles DNA-binding proteins involved in
plasmid partitioning and shares homology with ParB of bacteriophage P1 and
SopB of plasmid F.
Current models suggest that upon a shift to 37°C, H-NS is displaced from
the
virF
operator allowing VirF expression. H-NS is also displaced from the
virB
operator which allows VirF to bind and induce the expression of
virB
, which in
turn induces the expression of the
ipa, mxi,
and
spa
operons. These promoters
are sensitive to the level of VirB protein in the cell. They require a threshold
level of VirB to be reached to displace H-NS before becoming active (
Beloin and
Dorman, 2003
). VirB does not appear to recruit RNA polymerase but rather acts
as an anti-repressor of H-NS, freeing promoters for polymerase entry (
Turner
and Dorman, 2007
). Thus, binding of VirF may act as an antagonist to binding
by H-NS and thereby provides a mechanism for responding to temperature.
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