This Article Full Text Full Text (PDF) Other Versions of this Article: IAI.01004-07v1 76/3/1230    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hendriksen, W. T. Articles by Hermans, P. W. M. Search for Related Content PubMed PubMed Citation Articles by Hendriksen, W. T. Articles by Hermans, P. W. M.

 Previous Article  |  Next Article 

Infection and Immunity, March 2008, p. 1230-1238, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.01004-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Site-Specific Contributions of Glutamine-Dependent Regulator GlnR and GlnR-Regulated Genes to Virulence of Streptococcus pneumoniae

Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, 3000 DR Rotterdam, The Netherlands,¹ Department of Molecular Genetics, University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, P.O. Box 14, 9750 AA Haren, The Netherlands,² Laboratory of Pediatric Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands³

Received 23 July 2007/ Returned for modification 29 August 2007/ Accepted 20 December 2007

The transcriptional regulator GlnR of Streptococcus pneumoniae is involved in the regulation of glutamine and glutamate metabolism, controlling the expression of the glnRA and glnPQ-zwf operons, as well as the gdhA gene. To assess the contribution of the GlnR regulon to virulence, D39 wild-type and mutant strains lacking genes of this regulon were tested in an in vitro adherence assay and murine infection models. All of the mutants, except the glnR mutant, were attenuated in adherence to human pharyngeal epithelial Detroit 562 cells, suggesting a contribution of these genes to adherence during the colonization of humans. During murine colonization, only the glnA mutant and the glnP-glnA double mutant (glnAP) were attenuated, in contrast to glnP, indicating that the effect is caused by the lack of GlnA expression. In our pneumonia model, only glnP and glnAP showed a significantly reduced number of bacteria in the lungs and blood, indicating that GlnP is required for survival in the lungs and possibly for dissemination to the blood. In intravenously infected mice, glnP and glnA were individually dispensable for survival in the blood whereas the glnAP mutant was avirulent. Finally, transcriptome analysis of the glnAP mutant showed that many genes involved in amino acid metabolism were upregulated. This signifies the importance of glutamine/glutamate uptake and synthesis for full bacterial fitness and virulence. In conclusion, several genes of the GlnR regulon are required at different sites during pathogenesis, with glnA contributing to colonization and survival in the blood and glnP important for survival in the lungs and, possibly, efficient transition from the lungs to the blood.

Published ahead of print on 3 January 2008.

Editor: J. N. Weiser