Role of the extracytoplasmic‐function σ Factor σ^H in Mycobacterium tuberculosis global gene expression

Abstract

SummaryLike other bacterial species, Mycobacterium tuberculosis has multiple sigma (s) factors encoded in its genome. In previously published work, we and others have shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and, in some cases, cause attenuated virulence phenotypes. In this paper, we characterize a M. tuberculosis mutant lacking the ECF s factor s H . This mutant was more sensitive than the wild type to heat shock and to various oxidative stresses, but did not show decreased ability to grow inside macrophages. Using quantitative reverse transcription-PCR and microarray technology, we have started to define the s H regulon and its involvement in the global regulation of the response to heat shock and the thiol-specific oxidizing agent diamide. We identified 48 genes whose expression increased after exposure of M. tuberculosis to diamide; out of these, 39 were not induced in the sigH mutant, showing their direct or indirect dependence on s H . Some of these genes encode proteins whose predicted function is related to thiol metabolism, such as thioredoxin, thioredoxin reductase and enzymes involved in cysteine and molybdopterine biosynthesis. Other genes under s H control encode transcriptional regulators such as sigB, sigE, and sigH itself.

Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis

“…4a), which corresponds to the site previously reported (Manganelli et al, 2002;Raman et al, 2001). Activation of this TSP under SDS stress was MprA-dependent (Fig.…”

“…SigE is a major stress-responsive sigma factor of M. tuberculosis (Jensen-Cain & Quinn, 2001;Manganelli et al, 1999Manganelli et al, , 2001Raman et al, 2001), and often functions within a regulatory cascade (Manganelli et al, 2002;Raman et al, 2001). SDS exposure upregulates SigE, which then activates 23 genes, including sigB, mprA, mprB and four other transcription factor genes (Manganelli et al, 2001).…”

“…To withstand the challenges of aerosol transmission, growth within host macrophages, and prolonged encapsulation within lung granuloma, these organisms require the ability to respond to different types of stress. M. tuberculosis has 13 sigma factors (Cole et al, 1998), and DNA microarray analyses have shown the importance of several of these in regulating the changes in gene expression patterns associated with various stresses (Geiman et al, 2004;Manganelli et al, 2001Manganelli et al, , 2002. In addition to sigma factors, the response regulators of some two-component systems (TCSs) (Rison et al, 2005), such as DosR (Kendall et al, 2004;Park et al, 2003) and PhoP Perez et al, 2001;Walters et al, 2006), and other transcriptional regulators, such as IdeR (Dussurget et al, 1999;Manabe et al, 2005) and EmbR (Sharma et al, 2006), have been shown to modulate mycobacterial gene expression in response to particular stresses.…”

“…However, as some of the invariant residues reported for SigH-dependent promoters are missing (Manganelli et al, 2002;Raman et al, 2001), it is likely that another sigma factor regulates sigE from this promoter.…”

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

“…Recently, it was shown that this gene is also induced by rifamicin, and that RbpA is able to stimulate the expression of the rRNA operon even in the presence of rifamicin, conferring a basal level of resistance to this drug (Newell et al, 2006). In M. tuberculosis, Rv2050 was shown to be under the transcriptional control of SigH (SigR orthologue) and upregulated after heat shock and disulfide stress (Manganelli et al, 2002). The finding that the expression of this gene is also induced by vancomycin suggests that Rv2050 might contribute to the basal level of drug resistance in mycobacteria as well, opening the possibility to consider it as a novel drug-target candidate.…”