Bacterial Pathogenesis, Molecular Basis of
559
Finally, a bacterium can increase its
v
iru
lences
imp
lybyha
rbor
ingmu
ta
t
ions
in a gene required for pathogenic success.
There are numerous examples of such
a mechanism in action, but one of the
best is the
fmH
gene of
E. coli
,wh
i
ch
encodes a protein required for adherence
to host tissue. It has been shown that
various single mutations in the sequence
of this gene can give rise to variants of
the adhesin, which increase the binding
of the
E. coli
to tissue, thereby raising its
virulence potential.
Clearly, the mechanisms described in
the preceding text have implications for the
evolution of pathogenic bacteria. A given
organism may be the subject of one or
more of the mechanisms and may thereby
evolve into a more potent, ef±cient, and
ever-changing pathogen. In addition, the
ability of vectors such as bacteriophages
and plasmids to harbor virulence genes
and their potential as vectors for horizontal
transfer of virulence traits suggests that
bacteria are constantly evolving during
passage through their hosts.
4
Regulation of Virulence
As mentioned in the previous section,
pathogens produce an array of products
collectively termed
virulence Factors
,wh
ich
enable them to cause disease. However,
pathogens do not express these factors con-
stitutively. Rather, expression of most vir-
ulence factors is tightly controlled. Given
that a pathogen must be able to sense
the condition of its host, it is not surpris-
ing that many of the signals that initiate
expression of virulence factors are environ-
mental. Diverse bacterial pathogens can
recognize an array of signals including
pH, temperature, growth phase, osmolar-
ity, oxygen tension, and availability of iron
and carbon source as cues for virulence fac-
tor expression. By way of example, the Anr
protein is responsible for the modulation
of gene expression due to oxygen availabil-
ity in
P. aeruginosa
. There are a number
of regulatory factors that are responsive
to the presence or absence of iron. The
most recognized of these is the Fur pro-
tein that binds to speci±c DNA elements
only in the presence of iron, resulting in
the repression of the target gene(s). The
ability to sense such signals is critical to
the organisms’ ability to adapt to the mi-
croenvironment in which it ±nds itself.
The sensing of a speci±c signal results
in the triggering of a cascade of events
that lead to a regulation of the genes re-
sponsible for the production of a given
virulence factor(s). The signals are con-
verted to a speci±c response via the action
of molecules deemed regulators. In the
simplest sense, the regulators alter the
expression of a gene so that it is ei-
ther increased or decreased in response
to the signals that are sensed. Some of
these regulatory molecules may respond
to more than one signal, and, in this
way, the expression of various virulence
factors is coordinated and made interde-
pendent to allow the required response
of the organism. While the mechanism(s)
used to regulate gene expression are nu-
merous, they can be broadly categorized
into several common motifs. In addition,
a pathogen can use one or more mech-
anisms to simultaneously respond to the
signals that they sense. Furthermore, one
or more mechanisms may act to regulate
the production of a single virulence fac-
tor, allowing the pathogen to monitor and
respond to multiple environmental cues
to ±nely tune the expression of the given
factor. Although many diverse organisms
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