sigma R, an RNA polymerase sigma factor that modulates expression of the thioredoxin system in response to oxidative stress in Streptomyces coelicolor A3(2)

Paget, Mark S. B.

doi:10.1093/emboj/17.19.5776

Cited by 192 publications

(239 citation statements)

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“…The arrangement of genes at the M. tuberculosis sigH locus resembles that of the Streptomyces coelicolor A3(2) sigR locus (38,39), and it has been shown that the gene adjacent to sigR (rsrA) inhibits SigR activity by functioning as SigR-sequestering anti-factor (40). Because MT3318 transcriptional levels parallel those of sigH, it appears likely that the SigH and the MT3318 gene product are produced in equimolar quantities.…”

Section: Construction Of the Sigh Mutant And Complemented Strainmentioning

confidence: 99%

Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

Kaushal

Schroeder

Tyagi

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

220

228

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The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infection phenotype. In resistant C57BL͞6 mice, the mutant achieved high bacterial counts in lung and spleen that persisted in tissues in a pattern identical to those of wild-type bacteria. Despite a high bacterial burden, the mutant produced a blunted, delayed pulmonary inflammatory response, and recruited fewer CD4 ؉ and CD8 ؉ T cells to the lung in the early stages of infection. In susceptible C3H mice, the mutant again showed diminished immunopathology and was nonlethal at over 170 days after intravenous infection, in contrast to isogenic wild-type bacilli, which killed with a median time to death of 52 days. Complete genomic microarray analysis revealed that M. tuberculosis sigH may mediate the transcription of at least 31 genes directly and that it modulates the expression of about 150 others; the SigH regulon governs thioredoxin recycling and may be involved in the maintenance of intrabacterial reducing capacity. These data show that the M. tuberculosis sigH gene is dispensable for bacterial growth and survival within the host, but is required for the production of immunopathology and lethality. This phenotype demonstrates that beyond an ability to grow and persist within the host, M. tuberculosis has distinct virulence mechanisms that elicit deleterious host responses and progressive pulmonary disease.T uberculosis is one of the leading infectious causes of death and claims Ϸ2 million lives annually (1). There is controversy over whether the disease is primarily a dysfunctional immunologic reaction to a persistent microbe or whether the bacteria themselves produce tissue damage; there is evidence that both host and bacterial factors play key roles in disease severity. In susceptible mouse strains, such as C3H, the pathogen elicits a dysregulated, necrotizing host immune response leading to tissue destruction and further bacterial replication. In resistant mice such as C57BL͞6, Mycobacterium tuberculosis survives in high numbers for many months and is contained in organized granulomatous lesions in the lung without progressive lung damage. Thus whereas mycobacteria survive in both genetic backgrounds, disease progression is delayed in resistant animals (2-4).On the bacterial side, M. tuberculosis virulence has been associated with its initial survival within macrophages and resistance to reactive oxygen and nitrogen intermediates (ROIs and RNIs) (5-8). Tubercle bacilli demonstrate inducible responses to oxidative stresses, and several M. tuberculosis genes, including katG (catalase peroxidase), ahpC (alkylhydroperoxide reductase), and sodA and sodC (superoxide dismutases) have been implicated in protection from the macrophage oxidative burst (9-11). Another potential ...

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Section: Construction Of the Sigh Mutant And Complemented Strainmentioning

confidence: 99%

Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

Kaushal

Schroeder

Tyagi

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

220

228

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“…Thioredoxin and thioredoxin reductase of M. tuberculosis have been shown to reduce peroxides and dinitrobenzenes with higher efficiency under anaerobic conditions (Zhang et al, 1999). In Streptomyces coelicolor the trxB operon has been found to be controlled by SigR (Paget et al, 1998) and its homologue in M. tuberculosis is designated SigH. Several studies have indicated that the sigma factors SigB, SigE, SigF and SigH in M. tuberculosis and M. smegmatis are involved in adaptation to several stresses, including heat shock and oxidative stress (Chen et al, 2000;Fernandes et al, 1999;Hu & Coates, 1999;Manganelli et al, 1999).…”

Section: Stress Proteinsmentioning

confidence: 99%

Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions

Starck

Källenius

Marklund³

et al. 2004

Microbiology

136

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Data are presented from two-dimensional (2-D) PAGE analysis of Mycobacterium tuberculosis strain Harlingen grown during aerobic and anaerobic culture, according to a modified Wayne dormancy model. M. tuberculosis cultures were grown to the transition point between exponential growth and stationary phase in the presence of oxygen (7 days) and then part of the cultures was shifted to anaerobic conditions for 16 days. Growth declined similarly during aerobic and anaerobic conditions, whereas the ATP consumption rapidly decreased in the anaerobic cultures. 2-D PAGE revealed 50 protein spots that were either unique to, or more abundant during, anaerobic conditions and 16 of these were identified by MALDI-TOF. These proteins were the a-crystalline homologue (HspX), elongation factor Tu (Tuf), GroEL2, succinyl-CoA : 3-oxoacid-CoA transferase (ScoB), mycolic acid synthase (CmaA2), thioredoxin (TrxB2), b-ketoacyl-ACP synthase (KasB), L-alanine dehydrogenase (Ald), Rv2005c, Rv2629, Rv0560c, Rv2185c and Rv3866. Some protein spots were found to be proteolytic fragments, e.g. HspX and GroEL2. These data suggest that M. tuberculosis induces expression of about 1 % of its genes in response to dormancy. INTRODUCTIONHuman tuberculosis (TB) is caused by an intracellular pathogen, Mycobacterium tuberculosis, which causes both latent and acute illness. Approximately eight million active cases are reported annually with 2 million deaths. In addition, about one-third of the global population is estimated to suffer from latent tuberculosis (Dye et al., 1999), which can be reactivated even after several decades. The fact that the bacilli can shift into a dormant state is of therapeutic importance, since this dormant state induces resistance to the two most important TB-drugs, rifampicin and isoniazide (Wayne & Sramek, 1994). One of the most challenging problems in TB research is to reveal the mechanisms behind latency.Latency is believed to involve a non-replicating persistence of mycobacteria or a very slow growth. One important condition believed to contribute to latency is reduced access to oxygen. M. tuberculosis is generally regarded as a strictly aerobic bacillus, although it can survive for a long time in a micro-aerophilic environment as long as the shift is not too abrupt (Wayne & Hayes, 1996). An in vitro model to study this persistent state is the so-called Wayne dormancy model, in which the bacteria downregulate their metabolism due to reduced access to oxygen (Wayne & Hayes, 1996). Another dormancy model utilizes nutrient starvation to induce a state where M. tuberculosis arrests growth and decreases its respiration rate (Betts et al., 2002). Recently it was demonstrated that inhibition of respiration by nitric oxide might induce a dormant state in M. tuberculosis . One should recognize, however, that the evidence linking in vitro dormant states of M. tuberculosis to human latent infection still remains circumstantial.The vaccine strain Mycobacterium bovis BCG has been reported to occasionally persist in a latent state in ...

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“…Further evidence for the distinction between peroxide stress and disulphide stress has emerged from analysis of the Streptomyces coelicolor s R regulon (Paget et al, 2001a). Induction of the s R regulon with diamide activates transcription of thioredoxin and thioredoxin reductase, thereby acting to restore oxidized thiols in the cell to their appropriate reduced state (Paget et al, 1998). The activity of s R is regulated by RsrA, the cognate antis factor (Kang et al, 1999), which is a zinc metalloprotein that binds s R to form an inactive complex.…”

Section: Introductionmentioning

confidence: 99%

Regulation of inducible peroxide stress responses

Mongkolsuk¹,

Helmann²

2002

Molecular Microbiology

267

217

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Summary Bacteria adapt to the presence of reactive oxygen species (ROS) by increasing the expression of detoxification enzymes and protein and DNA repair functions. These responses are co‐ordinated by transcription factors that regulate target genes in response to ROS. We compare three classes of peroxide‐sensing regulators: OxyR, PerR and OhrR. In all three cases, peroxides effect changes in the redox status of cysteine residues, but the molecular details are distinct. OxyR is converted into a transcriptional activator by the formation of a disulphide bond between two reactive cysteine residues. PerR is a metalloprotein that functions as a peroxide‐ sensitive repressor. Oxidation is modulated by metal ion composition and may also involve disulphide bond formation. OhrR represses an organic peroxide resistance protein and mediates derepression in response to organic peroxides. Peroxide sensing in this system requires a single conserved cysteine, which is oxidized to form a cysteine–sulphenic acid derivative.

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sigma R, an RNA polymerase sigma factor that modulates expression of the thioredoxin system in response to oxidative stress in Streptomyces coelicolor A3(2)

Cited by 192 publications

References 40 publications

Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions

Regulation of inducible peroxide stress responses

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