Functional Genomics Reveals Extended Roles of the Mycobacterium tuberculosis Stress Response Factor σ H

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Abstract
Mycobacterium tuberculosis is one of the most successful pathogens of humankind. During infection, M. tuberculosis must cope with and survive against a variety of different environmental conditions. Sigma factors likely facilitate the modulation of the pathogen's gene expression in response to changes in its extracellular milieu during infection. σ H , an alternate sigma factor encoded by the M. tuberculosis genome, is induced by thiol-oxidative stress, heat shock, and phagocytosis. In response to these conditions, σ H induces the expression of σ B , σ E , and the thioredoxin regulon. In order to more effectively characterize the transcriptome controlled by σ H , we studied the long-term effects of the induction of σ H on global transcription in M. tuberculosis . The M. tuberculosis isogenic mutant of σ H (Δ-σ H ) is more susceptible to diamide stress than wild-type M. tuberculosis . To study the long-term effects of σ H induction, we exposed both strains to diamide, rapidly washed it away, and resumed culturing in diamide-free medium (post-diamide stress culturing). Analysis of the effects of σ H induction in this experiment revealed a massive temporal programming of the M. tuberculosis transcriptome. Immediately after the induction of σ H , genes belonging to the functional categories “virulence/detoxification” and “regulatory proteins” were induced in large numbers. Fewer genes belonging to the “lipid metabolism” category were induced, while a larger number of genes belonging to this category were downregulated. σ H caused the induction of the ATP-dependent clp proteolysis regulon, likely mediated by a transcription factor encoded by Rv2745c, several members of the mce1 virulence regulon, and the sulfate acquisition/transport network.