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Journal of Bacteriology, January 2008, p. 590-601, Vol. 190, No. 2
0021-9193/08/$08.00+0     doi:10.1128/JB.00917-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CodY of Streptococcus pneumoniae: Link between Nutritional Gene Regulation and Colonization{triangledown}

Wouter T. Hendriksen,1 Hester J. Bootsma,2 Silvia Estevão,1 Theo Hoogenboezem,1 Anne de Jong,3 Ronald de Groot,2 Oscar P. Kuipers,3 and Peter W. M. Hermans2*

Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, 3000 DR Rotterdam, The Netherlands,1 Laboratory of Pediatric Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands,2 Department of Molecular Genetics, University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, 9750 AA Haren, The Netherlands3

Received 12 June 2007/ Accepted 6 November 2007

CodY is a nutritional regulator mainly involved in amino acid metabolism. It has been extensively studied in Bacillus subtilis and Lactococcus lactis. We investigated the role of CodY in gene regulation and virulence of the human pathogen Streptococcus pneumoniae. We constructed a codY mutant and examined the effect on gene and protein expression by microarray and two-dimensional differential gel electrophoresis analysis. The pneumococcal CodY regulon was found to consist predominantly of genes involved in amino acid metabolism but also several other cellular processes, such as carbon metabolism and iron uptake. By means of electrophoretic mobility shift assays and DNA footprinting, we showed that most of the targets identified are under the direct control of CodY. By mutating DNA predicted to represent the CodY box based on the L. lactis consensus, we demonstrated that this sequence is indeed required for in vitro DNA binding to target promoters. Similar to L. lactis, DNA binding of CodY was enhanced in the presence of branched-chain amino acids, but not by GTP. We observed in experimental mouse models that codY is transcribed in the murine nasopharynx and lungs and is specifically required for colonization. This finding was underscored by the diminished ability of the codY mutant to adhere to nasopharyngeal cells in vitro. Furthermore, we found that pcpA, activated by CodY, is required for adherence to nasopharyngeal cells, suggesting a direct link between nutritional regulation and adherence. In conclusion, pneumococcal CodY predominantly regulates genes involved in amino acid metabolism and contributes to the early stages of infection, i.e., colonization of the nasopharynx.

* Corresponding author. Mailing address: Laboratory of Pediatric Infectious Diseases, Radboud University Nijmegen Medical Centre, P.O. Box 9101 (Route 224), 6500 HB Nijmegen, The Netherlands. Phone: (31)-24-3666406. Fax: (31)-24-3666352. E-mail: P.Hermans{at}cukz.umcn.nl

{triangledown} Published ahead of print on 16 November 2007.

Journal of Bacteriology, January 2008, p. 590-601, Vol. 190, No. 2
0021-9193/08/$08.00+0     doi:10.1128/JB.00917-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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