Gene regulation in Streptococcus pneumoniae - RePub - Erasmus ...

Chapter 8
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Being one of the major asymptomatic inhabitants of the human upper respiratory tract,
Streptococcus pneumoniae is also one of the major pathogens to cause various infections,
ranging from otitis media (middle ear infection) to bacteremia (blood infection). The currently
available 7-valent conjugate vaccine directed against the polysaccharide capsule is effective
but has the major drawback of only protecting against a select group of serotypes (defined by
their different composition of polysaccharide capsule). Consequently, a considerable part of
recent pneumococcal research focuses on identifying suitable protein targets as vaccine
antigens. However, this approach is dependent on expression of such proteins at the site of
infection. For this reason, the following questions need to be addressed: Which proteins are
expressed? When are these proteins expressed? How are the genes encoding these proteins
regulated under different conditions? Which nutrients are used when the bacterium resides,
for instance, in the nasopharynx or in the lungs? and of course, What exactly triggers
expression of genes required for virulence? The research described in this thesis has
contributed to a better understanding of the basic biology of the pneumococcus by focusing
on (nutritional) regulatory systems that control expression of various proteins that are directly
or indirectly involved in virulence. Specifically, we examined the two component system 09
and the transcriptional regulators PsaR, CodY, and GlnR.
Two-component signal transduction systems (TCSs) play an important role in
pneumococcal physiology by regulating various cellular processes (22, 33). They sense
environmental stimuli that, when present, activate a signaling cascade. As was previously
shown by Blue and Mitchell, response regulator 09 (rr09) has a strain-specific role in
virulence in mice: an rr09 mutant of D39 (serotype 2) was found to be avirulent in all models
tested (i.e., colonization, pneumonia, and bacteremia), while an rr09 mutant in 0100993
(serotype 3) was only attenuated upon intranasal infection (3). We extended these
observations to TIGR4 (serotype 4) and showed that TIGR4 RR09 is also required for full
virulence upon intranasal infection (chapter 2 and 15). In addition, we showed that TCS09
controls expression of different sets of genes in D39 and TIGR4. Taken together, these
observations suggested that the different virulence properties of these strains might, at least
partially, be explained by this differential RR09-regulated gene expression. Especially the
operon encoding a putative phosphotransferase system (sp0060-sp0066) was found to be
differentially expressed between D39, TIGR4, and 0100993. Interestingly, expression of this
operon appeared to coincide with the virulence properties of the respective strains (i.e.,
downregulation of sp0063 in D39∆rr09 and no differential expression in TIGR4∆rr09).
However, a D39∆sp0063 mutant was not attenuated in a murine model of infection, indicating