| Autor: |
Grosse-Siestrup BT; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Gupta T; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Helms S; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Tucker SL; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Voskuil MI; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Quinn FD; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA., Karls RK; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA. |
| Abstrakt: |
Sigma factor C (SigC) contributes to Mycobacterium tuberculosis virulence in various animal models, but the stress response coordinated by this transcription factor was undefined. The results presented here indicate that SigC prevents copper starvation. Whole genome expression studies demonstrate short-term (4-h) induction of sigC , controlled from a tetracycline-inducible promoter, upregulates ctpB and genes in the nonribosomal peptide synthase ( nrp ) operon. These genes are expressed at higher levels after 48-h sigC induction, but also elevated are genes encoding copper-responsive regulator RicR and RicR-regulated copper toxicity response operon genes rv0846-rv0850 , suggesting prolonged sigC induction results in excessive copper uptake. No growth and global transcriptional differences are observed between a sigC null mutant relative to its parent strain in 7H9 medium. In a copper-deficient medium, however, growth of the sigC deletion strain lags the parent, and 40 genes (including those in the nrp operon) are differentially expressed. Copper supplementation reverses the growth defect and silences most transcriptional differences. Together, these data support SigC as a transcriptional regulator of copper acquisition when the metal is scarce. Attenuation of sigC mutants in severe combined immunodeficient mice is consistent with an inability to overcome innate host defenses that sequester copper ions to deprive invading microbes of this essential micronutrient. |
