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

Chapter 6
Abstract
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The transcriptional regulator GlnR of Streptococcus pneumoniae is involved in the
regulation of glutamine and glutamate metabolism, controlling the expression of the glnRA
and glnPQ-zwf operons as well as the gdhA gene. To assess the contribution of the GlnR-
regulon to virulence, D39 wild-type and mutants lacking genes of this regulon were tested in
an in vitro adherence assay and murine infection models. All mutants, except ΔglnR, were
attenuated in adherence to human pharyngeal epithelial Detroit 562 cells, suggesting
contribution of these genes to adherence during colonization of humans. During murine
colonization only the ΔglnA and glnP-glnA double mutant (ΔglnAP) were attenuated, in
contrast to ΔglnP, indicating that the effect is caused by the lack of GlnA expression. In our
pneumonia model, only ΔglnP and ΔglnAP showed a significantly reduced number of
bacteria in the lungs and in blood, indicating that GlnP is required for survival in the lungs
and possibly for dissemination to the blood. In intravenously infected mice, glnP and glnA are
individually dispensable for survival in the blood, whereas ∆glnAP was avirulent. Finally,
transcriptome analysis of the ∆glnAP showed that many genes involved in amino acid
metabolism were upregulated. This signifies the importance of glutamine / glutamate uptake
and synthesis for full bacterial fitness and virulence. In conclusion, several genes of the GlnR-
regulon are required at different sites during pathogenesis, with glnA contributing to
colonization and survival in the blood and glnP important for survival in the lungs and,
possibly, efficient transition from the lungs to the blood.