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

metabolism are often required for virulence. For instance, in Staphylococcus aureus
production of capsular polysaccharides and toxigenic exoproteins is repressed under
carbohydrate-rich conditions, while adhesion factors are expressed (see 56 for review).
Similarly, Clostridium difficile toxin production is associated with severe changes in
metabolism (26). This co-regulation suggests that bacteria may become pathogenic when the
nutritional supply decreases. By damaging the host tissue new nutrients can become available
for these bacteria.
Introduction
Availability of nitrogen is of high importance since this element is present in most
building blocks of the bacterial cell, such as for instance DNA, RNA, and proteins.
Regulation of uptake of nitrogen-containing molecules is therefore essential for the fitness of
the bacterium. In many Gram-positive bacteria, CodY is one of the main transcriptional
regulators responsible for controlling the activity of systems that take up or process nitrogencontaining
compounds (40, 57). This protein is responsive to the presence of the branched
chain amino acids (BCAAs) isoleucine, valine, and leucine. When present in high enough
concentrations, BCAAs interact with CodY, which results in DNA-binding of CodY to
conserved regions in the target promoters where it represses gene activity (Fig 3). In Bacillus
subtilis, an additional molecule, GTP, modulates the repressive activity of CodY. In contrast,
in lactic acid bacteria (to which pneumococci belong) it has been shown that CodY is not
responsive to GTP (13). This difference might reflect the considerable physiological
difference between these bacteria.
In addition to CodY, the transcriptional regulator GlnR also controls the expression of
genes involved in nitrogen metabolism in B. subtilis (58, 59). GlnR specifically regulates
glutamine/glutamate metabolism. These two amino acids form the major donors of nitrogen to
the cell. GlnR controls the expression of GlnA, a metabolic enzyme converting glutamate in
glutamine (58, 59). Together, CodY and GlnR form the core of nitrogen regulators in B.
subtilis and for this reason we believe these might be important for pneumococcus as well.
Furthermore, metal cations are essential for bacterial survival. Ions such as Fe 2+ , Zn 2+ ,
Mg 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Mn 2+ are often required as co-factors for enzymatic activity. In
addition, these cations also differ in concentrations in the human body, where they may
trigger expression of virulence factors (29, 45). Pneumococcal transcriptional regulators like
SczA, RitR, and PsaR have been shown to be crucial for regulation of intracellular divalent
cation concentrations and virulence (25, 28, 29, 62, 63). The zinc response regulator SczA
regulates the expression of czcD, encoding a cation diffusion facilitator which offers
resistance to high Zn 2+ concentrations (28). In addition, the orphan response regulator RitR
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