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

Introduction
PsaR and pneumococcal virulence
Streptococcus pneumoniae encounters different environments during its life cycle: in
most cases it inhabits the human nasopharynx where it resides asymptomatically, but it can
also spread through the body, causing severe infections (5). What exactly triggers the
pneumococcus to cause infections at these sites in the body is poorly understood. In response
to environmental changes, the transcriptional program is likely to change, which is considered
to be niche-specific and can result in expression of distinct virulence factors.
Manganese ions (Mn 2+ ) are important for bacterial life, for instance serving as
cofactors for metalloenzymes. The function of these metalloenzymes is widespread among
bacterial cellular processes, such as glycolysis, gluconeogenesis, and oxidative stress defense
(26). In pneumococcus, involvement of Mn 2+ in competence has also been described (12), but
most studies have focused on its involvement in oxidative stress (25, 28, 39, 40, 42, 48). In
the latter process, Mn 2+ serves as a cofactor for superoxide dismutase, an important enzyme
that provides defense against superoxide radicals (3). As the concentration of manganese is
much higher in saliva than in blood plasma (9), fluctuations in the amount of this trace
element might serve as a trigger for expression of certain virulence factors.
Various transcriptional regulators have been described for the pneumococcus (20) and
several large scale mutagenesis studies have identified a role in virulence for these regulators
(8, 18, 21, 36, 43). One of them is encoded by psaR, a transcriptional regulator responsive to
Mn 2+ and negatively affecting the expression of the psa operon, pcpA, rlrA, and prtA (28, 32).
Recently, the PsaR-binding sequence was identified in the promoter region of psaBCA, prtA,
and pcpA, and a genome-wide screen for this binding sequence did not show any other
putative targets (31). Moreover, it has been reported that regulation by PsaR is opposite in
reaction to two cations, namely repression in high Mn 2+ and derepression in high Zn 2+ (32).
The pcpA gene encodes a choline binding protein (46) and rlrA encodes a
transcriptional regulator, which controls the expression of the rlrA pathogenicity islet (19).
The psaBCA operon encodes the Psa permease that transports the cations Mn 2+ and Zn 2+ into
the cell (12, 28, 29, 37, 39). The permease has been implicated in virulence and protection
against pneumococcal infection (6, 47). Moreover, PsaA has been shown to bind to Ecadherin,
a surface molecule of the host cells (2, 44, 45). PsaR homologues are found in other
streptococci, where they regulate homologues of psaBCA and contribute to virulence (17, 27,
41). The role of PsaR in pneumococcal virulence has been investigated in an EF3030
(serotype 19F) genetic background (28). During seven days of colonization no difference
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