genomewide characterization of host-pathogen interactions by ...

Maren Depke
Introduction
Mechanisms of S. aureus Adaptation to its Environment
For its survival in changing environments, the bacterium needs an adaptive response and thus
an effective regulation of all cellular processes including gene expression, protein synthesis, and
turnover allowing adaptation to different conditions. Such regulation not only controls cell
division and metabolism, but also systems for exploiting limited nutrients, adaptation of the
composition of the cell wall as outer boundary, surface factors like adhesins, and systems
rendering stress resistance and guaranteeing endurance in situations non-favorable for growth or
survival. In bacteria, the regulation often affects the transcription of genes as starting point for
changes in the following levels like protein synthesis. Two-component systems (TCS) mediate the
sensing of environmental signals with the sensor component and the adequate reaction with the
response regulator component. An example for such TCS is the agr system. Additionally,
transcription factors like SarA modulate staphylococcal gene expression (Cheung et al. 2004).
Another well-conserved system is the use of alternative sigma factors. Transcription in
bacteria is only initiated when the catalytic core complex of RNA polymerase, formed of the five
subunits α 2 ββ’ω, is associated with a sigma factor recognizing the promoter (-10/-35-region). A
so-called house-keeping sigma factor (in S. aureus: σ A ; Deora/Misra 1995) maintains the baseline
expression of a “standard” set of genes that is generally needed by the cell. Alternative sigmafactors
are activated in specific situations, e. g. after heat shock or salt stress. They recognize a
specific set of promoters of genes whose function is required to encounter the corresponding
physiological conditions. This set of genes includes further transcriptional regulators which
themselves positively or negatively influence the expression of genes depending on the need of
the bacterial cell. S. aureus possesses three alternative sigma factors: σ B , σ H , and − most recently
discovered − σ S (Wu et al. 1996; Morikawa et al. 2003; Shaw et al. 2008). SigB is homologous to
sigB of Bacillus subtilis which has been subjected to intensive studies. Despite the similarity of
sigB in B. subtilis and S. aureus, only half of the gene cluster coding for proteins belonging to the
control cascade of SigB activation/inactivation (rsbU-rsbV-rsbW-sigB) is conserved in S. aureus. Of
special importance is the gene rsbU, coding for the phosphatase that is the starting point for
activation of the alternative sigma factor SigB. After dephosphorylation by RsbU the anti-antisigma
factor RsbV becomes active and binds RsbW leading to liberation of SigB from its antisigma
factor RsbW. Contrarily to B. subtilis where further rsb gene products are regulators of
RsbU activity, in S. aureus an increase in RsbU already leads to SigB activation (Senn et al. 2005).
Deletion of sigB in S. aureus leads among other things to a loss of pigmentation, increased
sedimentation rate and increased sensitivity to hydrogen peroxide in the stationary growth
phase. Different effects are observed on the expression of genes and on the abundance of
proteins. On the one hand some proteins are missing in sigB deletion mutants (e. g. Asp23) that
are directly regulated and transcribed by SigB. On the other hand, other proteins have a higher
abundance in the sigB deletion mutants (e. g. lipase, thermonuclease). For such genes a negative
regulation by SigB itself or a SigB controlled regulator is basis of the regulation observed (Kullik et
al. 1998). Bischoff et al. (2004) propose YabJ, SpoVG, SarA, SarS and ArlRS as regulators possibly
responsible for the indirect SigB effects.
The SigB regulon in S. aureus has some similarities to that of B. subtilis, but the main function
to obtain a broad-range stress resistance to the triggering stimulus and in advance also to other
stressors is not conserved in S. aureus. Energy and ethanol stress do not trigger a SigB response
in S. aureus. Nevertheless, some stress conditions such as heat shock, MnCl 2 , NaCl and alkaline
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