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

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. σH , an alternate sigma factor encoded by theM. tuberculosis genome, is induced by thiol-oxidative stress, heat shock, and phagocytosis. In response to these conditions, σH induces the expression of σB , σE , and the thioredoxin regulon. In order to more effectively characterize the transcriptome controlled by σH , we studied the long-term effects of the induction of σH on global transcription inM. tuberculosis . TheM. tuberculosis isogenic mutant of σH (Δ-σH ) is more susceptible to diamide stress than wild-typeM. tuberculosis . To study the long-term effects of σH 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 σH induction in this experiment revealed a massive temporal programming of theM. tuberculosis transcriptome. Immediately after the induction of σH , 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. σH caused the induction of the ATP-dependentclp proteolysis regulon, likely mediated by a transcription factor encoded by Rv2745c, several members of themce1 virulence regulon, and the sulfate acquisition/transport network.