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

CodY was found to be required for adherence and colonization (12 and chapter 4).
Many transport systems involved in nitrogen uptake and metabolism were found to be
regulated by CodY. A changed expression of one of these genes (or a combination of these)
might be responsible for the lack-of-colonization phenotype and the lower adherence of the
codY mutant. The pcpA gene was more highly expressed in the codY mutant, however, as
described above, it seems not very likely that this gene is required for colonization and
adherence.
Summarizing discussion
The transcriptional regulator GlnR was investigated in chapters 5 and 6. This
glutamine/glutamate-dependent regulator itself was found not to be essential for
pneumococcal virulence in mice, but its target genes were: glutamine synthetase GlnA was
required for efficient colonization and the glutamine permease GlnP was required for survival
in the lungs (14). A double mutant for glnA and glnP appeared to be avirulent in all our
models. Interestingly, microarray analysis showed that in this double mutant many CodY
targets were overexpressed, indicating that the double mutant was in severe nutritional stress.
Our results clearly show that both the CodY and GlnR regulatory systems are important for
pneumococcal virulence. Given the strain-specificity observed by us and others for other
regulatory systems, it will be interesting to see if these two highly conserved regulatory
proteins also have strain-specific features.
Concluding remarks
In this thesis four different regulatory systems have been investigated. In different
ways, all were shown to be involved in virulence. A major finding in this thesis is that the
target genes of several conserved regulators appear to be strain-specific (chapters 2 and 3),
which is rather surprising considering that these regulatory systems are conserved among the
sequenced strains and even among other streptococci. Strain-specificity complicates the
discovery of new antigens that could serve as novel vaccine targets. Besides strain-specific
regulation of gene expression, genes are also expressed site-specifically, e.g., expressed at the
nasopharynx but not in the blood. One can argue that for vaccination purposes, the ideal
situation would be expression of an antigen only during invasive disease and not during
colonization; this will leave colonization unaffected and will prevent invasive disease. The
benefit of leaving colonization unaffected is that it keeps other potentially pathogenic bacteria
from colonizing due to competition between pneumococcus and other respiratory pathogens
(4, 23).
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