Functional genomics reveals extended roles of the Mycobacterium tuberculosis stress response factor sigmaH.

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. sigma(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, sigma(H) induces the expression of sigma(B), sigma(E), and the thioredoxin regulon. In order to more effectively characterize the transcriptome controlled by sigma(H), we studied the long-term effects of the induction of sigma(H) on global transcription in M. tuberculosis. The M. tuberculosis isogenic mutant of sigma(H) (Delta-sigma(H)) is more susceptible to diamide stress than wild-type M. tuberculosis. To study the long-term effects of sigma(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 sigma(H) induction in this experiment revealed a massive temporal programming of the M. tuberculosis transcriptome. Immediately after the induction of sigma(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. sigma(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.