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Journal of Bacteriology, August 2008, p. 5382-5393, Vol. 190, No. 15
0021-9193/08/$08.00+0     doi:10.1128/JB.00307-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Opposite Effects of Mn²⁺ and Zn²⁺ on PsaR-Mediated Expression of the Virulence Genes pcpA, prtA, and psaBCA of Streptococcus pneumoniae

Tomas G. Kloosterman, Robert M. Witwicki, Magdalena M. van der Kooi-Pol, Jetta J. E. Bijlsma, and Oscar P. Kuipers^*

Department of Molecular Genetics, University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, P.O. Box 14, 9750 AA Haren, The Netherlands

Received 28 February 2008/ Accepted 22 May 2008

Homeostasis of Zn²⁺ and Mn²⁺ is important for the physiology and virulence of the human pathogen Streptococcus pneumoniae. Here, transcriptome analysis was used to determine the response of S. pneumoniae D39 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 the prtA, pcpA, and psaB promoters was stimulated by Mn²⁺, whereas Zn²⁺ destroyed the interaction of PsaR with its target promoters. Mutational analysis of the pcpA promoter 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 in S. pneumoniae, suggesting that the ratio of these metal ions exerts an important influence on pneumococcal pathogenesis.

Published ahead of print on 30 May 2008.

Present address: Molecular Bacteriology, Department of Medical Microbiology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.