A Role for Mycobacterium tuberculosis Sigma Factor C in Copper Nutritional Immunity

Sigma factor C (SigC) contributes to <i>Mycobacterium tuberculosis</i> 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 <i>sigC</i>, controlled from a tetracycline-inducible promoter, upregulates <i>ctpB</i> and genes in the nonribosomal peptide synthase (<i>nrp</i>) operon. These genes are expressed at higher levels after 48-h <i>sigC</i> induction, but also elevated are genes encoding copper-responsive regulator RicR and RicR-regulated copper toxicity response operon genes <i>rv0846-rv0850</i>, suggesting prolonged <i>sigC</i> induction results in excessive copper uptake. No growth and global transcriptional differences are observed between a <i>sigC</i> null mutant relative to its parent strain in 7H9 medium. In a copper-deficient medium, however, growth of the <i>sigC</i> deletion strain lags the parent, and 40 genes (including those in the <i>nrp</i> 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 <i>sigC</i> 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.