560
Bacterial Pathogenesis, Molecular Basis of
use a variety of regulators, many of these
regulators can be grouped into families
on the basis of their function. Thus, al-
though homologies at the sequence level
(both nucleotide and protein) may occur,
functionally the products are the same.
The number of regulators identiFed has
exploded with the introduction of molec-
ular techniques and their application to
studies of bacterial pathogenesis. While all
of them cannot be discussed here, it is im-
por
tan
ttoacqua
in
tthereaderw
i
thsome
examples and hence three major regula-
tory mechanisms are briefly described in
the following text.
One of the simplest ways to regulate the
expression of a speciFc gene is to alter the
recognition of the promoter elements rec-
ognized by RNA polymerase (the enzyme
responsible for synthesis of RNA from
DNA). Sigma factors, synthesized by most
bacteria regardless of pathogenic potential,
are proteins whose function is to interact
with RNA polymerase and thereby alter the
expression of a given gene(s). Many organ-
isms express various sigma factors, which
are responsible for coordinating gene ex-
pression to various speciFc environmental
cues. Not all organisms will produce the
same sigma factors, but the role of sigma
f
a
c
to
r
sa
sr
egu
l
a
to
r
so
fg
en
ee
xp
r
e
s
s
ion
has been well documented in many bacte-
ria. These factors may be produced during
speciFc periods of growth of the organism
or in response to speciFc stimuli. One ex-
cellent example is the sigma factor RpoS
(also known as
σ
32
). This sigma factor
has been shown to be important for the
virulence of a number of organisms includ-
ing
E. coli
,
Salmonella typhimurium
,and
P.
aeruginosa
. RpoS is expressed during the
stationary phase of growth when the or-
ganism is under various stresses such as
nutrient deprivation and oxygen tension.
Other sigma factors, which have a demon-
strated role in the expression of virulence
genes, are RpoE, which responds to various
stresses and is important for the virulence
of
S. typhimurium
;andRpoH
,wh
i
chi
s
involved in the heat shock response of
many organisms. The production of the
exopolysaccharide alginate, responsible for
the mucoid phenotype of
P. aeruginosa
in
infections of individuals with cystic Fbro-
sis, is regulated by two sigma factors RpoN
and AlgU.
One of the most common types of
regulator is that which belongs to the
two-component systems. These regulatory
systems consist of two proteins – a sensor
protein, which is embedded in the mem-
braneo
fthebac
ter
ia
lce
l
lwa
l
landwh
ich
acts to sense speciFc signals; and a re-
sponse regulator, which is then the media-
tor of the regulatory response. The sensor
molecules usually contain a histidine ki-
nase function that allows the molecule to
phosphorylate itself when a speciFc signal
is sensed. The phosphate is then trans-
ferred to the response regulator, which
alters its conformation and leads to the for-
mation of an ‘‘active’’ form of the molecule.
The response regulator may then either in-
teract with the RNA polymerase enzyme
or bind to the promoter region to result
in stimulation or repression of the gene
of interest. Two-component systems are
involved in the sensing of and response
to signals such as iron availability, car-
bon and nitrogen levels, and phosphate
levels. The expression of many different
virulence factors is known to be regu-
lated by two-component systems. Among
these are the
Bordetella pertussis
toxin, Fm-
briae and Flamentous hemagglutinin ±ha
(controlled by the BvgA/BvgS system),
the formation of pili and toxin in
Vib-
rio cholerae
(the ToxR/ToxS system), and
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