Abstract
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.
Highlights
Mycobacterium tuberculosis is the primary cause of death in humans by a single bacterial pathogen
sigma factor C (SigC) is fully conserved in M. tuberculosis strains CDC1551 and H37Rv, and in M. bovis BCG, none of the genes defined as members of the SigC regulon by transcriptome analyses of a CDC1551 sigC mutant [7] were upregulated after 18-h induction of sigC controlled from a tetracycline-inducible promoter in strain H37Rv [10] nor were any found with upstream promoters bound by SigC-RNA polymerase in M. bovis BCG chromosome immunoprecipitation/DNA microarray studies [11]
Absence of Significant Growth or Global Gene Expression Differences after Deletion of sigC from M. tuberculosis Strain Erdman Cultured in 7H9 Medium
Summary
Mycobacterium tuberculosis is the primary cause of death in humans by a single bacterial pathogen. Phenotypes and gene expression associated with sigC were examined in derivatives of M. tuberculosis strain Erdman. The term nutritional immunity was first used to define host processes of iron sequestration to prevent the growth of invading microbes [14], but subsequently expanded to encompass host sequestration of any essential trace metal from potential pathogens (reviewed in [15]). All saturation transposon mutagenesis studies indicate ctaD (rv3043), encoding cytochrome aa subunit 1 that contains the copper-B catalytic site, is an essential gene in M. tuberculosis [18,19,20]. The data presented support SigC as a transcription factor required by the obligate human pathogen M. tuberculosis to acquire copper from environments where levels of the free metal are very low
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