Opposite Effects of Mn2+and Zn2+on PsaR-Mediated Expression of the Virulence GenespcpA,prtA, andpsaBCAofStreptococcus pneumoniae

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Abstract
Homeostasis of Zn2+and Mn2+is important for the physiology and virulence of the human pathogenStreptococcus pneumoniae. Here, transcriptome analysis was used to determine the response ofS. pneumoniaeD39 to a high concentration of Zn2+. Interestingly, virulence genes encoding the choline binding protein PcpA, the extracellular serine protease PrtA, and the Mn2+uptake system PsaBC(A) were strongly upregulated in the presence of Zn2+. Using random mutagenesis, a previously described Mn2+-responsive transcriptional repressor, PsaR, was found to mediate the observed Zn2+-dependent derepression. In addition, PsaR is also responsible for the Mn2+-dependent repression of these genes. Subsequently, we investigated how these opposite effects are mediated by the same regulator. In vitro binding of purified PsaR to theprtA,pcpA, andpsaBpromoters was stimulated by Mn2+, whereas Zn2+destroyed the interaction of PsaR with its target promoters. Mutational analysis of thepcpApromoter demonstrated the presence of a PsaR operator that mediates the transcriptional effects. In conclusion, PsaR is responsible for the counteracting effects of Mn2+and Zn2+on the expression of several virulence genes inS. pneumoniae, suggesting that the ratio of these metal ions exerts an important influence on pneumococcal pathogenesis.

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