Rv3134c/devR/devS operon of Mycobacterium bovis BCG is differentially transcribed under “in vitro” stress conditions

Rodríguez, Juan Germán; Burbano, Claudia Sofía; Núñez, Claudio; González, Clara Eugenia; Zambrano, María Mercedes; García, María Jesús García; Portillo, Patricia Del

doi:10.1016/j.tube.2007.11.011

Cited by 9 publications

(8 citation statements)

References 36 publications

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“…Interestingly, five of the members of the lipid signature belong to the DosR hypoxia regulon. This suggests that induction of the DosR transcriptional regulator could result from cotranscription from the upstream Rv3134c gene (45, 46), which is part of the lipid signature. The Rv3134c gene harbors a usp domain, as does another gene of the lipid signature, Rv1996.…”

Section: Resultsmentioning

confidence: 99%

Global Adaptation to a Lipid Environment Triggers the Dormancy-Related Phenotype of Mycobacterium tuberculosis

Rodríguez

Hernández

Helguera-Repetto

et al. 2014

mBio

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103

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Strong evidence supports the idea that fatty acids rather than carbohydrates are the main energy source of Mycobacterium tuberculosis during infection and latency. Despite that important role, a complete scenario of the bacterium’s metabolism when lipids are the main energy source is still lacking. Here we report the development of an in vitro model to analyze adaptation of M. tuberculosis during assimilation of long-chain fatty acids as sole carbon sources. The global lipid transcriptome revealed a shift toward the glyoxylate cycle, the overexpression of main regulators whiB3, dosR, and Rv0081, and the increased expression of several genes related to reductive stress. Our evidence showed that lipid storage seems to be the selected mechanism used by M. tuberculosis to ameliorate the assumed damage of reductive stress and that concomitantly the bacilli acquired a slowed-growth and drug-tolerant phenotype, all characteristics previously associated with the dormant stage. Additionally, intergenic regions were also detected, including the unexpected upregulation of tRNAs that suggest a new role for these molecules in the acquisition of a drug-tolerant phenotype by dormant bacilli. Finally, a set of lipid signature genes for the adaptation process was also identified. This in vitro model represents a suitable condition to illustrate the participation of reductive stress in drugs’ activity against dormant bacilli, an aspect scarcely investigated to date. This approach provides a new perspective to the understanding of latent infection and suggests the participation of previously undetected molecules.

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Section: Resultsmentioning

confidence: 99%

Global Adaptation to a Lipid Environment Triggers the Dormancy-Related Phenotype of Mycobacterium tuberculosis

Rodríguez

Hernández

Helguera-Repetto

et al. 2014

mBio

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103

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“…5), suggesting that the transcripts are unstable or that the expression of rel genes is driven from multiple promoters. Such complex regulation has been demonstrated for the Mycobacterium bovis BCG Rv3134c/devR/devS operon, with three promoters exhibiting differential activity under hypoxia and nutrient starvation conditions (40). Further, two toxins and one antitoxin are expressed 110 h after macrophage infection.…”

Section: Discussionmentioning

confidence: 94%

Three Mycobacterium tuberculosis Rel Toxin-Antitoxin Modules Inhibit Mycobacterial Growth and Are Expressed in Infected Human Macrophages

Korch¹,

Contreras²,

Clark‐Curtiss

2009

J Bacteriol

102

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Mycobacterium tuberculosis protein pairs Rv1246c-Rv1247c, Rv2865-Rv2866, and Rv3357-Rv3358, here named RelBE, RelFG, and RelJK, respectively, were identified based on homology to the Escherichia coli RelBE toxin:antitoxin (TA) module. In this study, we have characterized each Rel protein pair and have established that they are functional TA modules. Overexpression of individual M. tuberculosis rel toxin genes relE, relG, and relK induced growth arrest in Mycobacterium smegmatis; a phenotype that was completely reversible by expression of their cognate antitoxin genes, relB, relF, and relJ, respectively. We also provide evidence that RelB and RelE interact directly, both in vitro and in vivo. Analysis of the genetic organization and regulation established that relBE, relFG, and relJK form bicistronic operons that are cotranscribed and autoregulated, in a manner unlike typical TA modules. RelB and RelF act as transcriptional activators, inducing expression of their respective promoters. However, RelBE, RelFG, and RelJK (together) repress expression to basal levels of activity, while RelJ represses promoter activity altogether. Finally, we have determined that all six rel genes are expressed in broth-grown M. tuberculosis, whereas relE, relF, and relK are expressed during infection of human macrophages. This is the first demonstration of M. tuberculosis expressing TA modules in broth culture and during infection of human macrophages.

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“…This conclusion is supported by the northern blot analysis which showed multiple mRNA transcripts corresponding to differential gene expression within the operon (Fig 1B), and the fact that the degree to which each of these genes is transcribed is dependent on the inducing agent [32]. In addition, the data indicate that the recA gene, although expressed as part of an operon with the two upstream genes under normal growth conditions (Fig 1B) [7], can be induced much more strongly than the others under both stress conditions (Fig 2B).…”

Section: Resultsmentioning

confidence: 75%

“…This phenomenon, termed a “conditional operon”, has been described in Mycobacterium bovis BCG in the Rv3134c/devR/devS operon where at least 3 different promoters have been identified for controlling expression under different conditions. Rv3134c and devR are only co-transcribed under hypoxia, while devR and devS are co-transcribed under hypoxic and starvation conditions [32]. In addition, the lolA and trxB genes of the TrxB operon of B. fragilis showed differential regulation at the transcriptional level [31].…”

Section: Resultsmentioning

confidence: 99%

The recA operon: A novel stress response gene cluster in Bacteroides fragilis

Nicholson

Smalley

Smith

et al. 2014

Research in Microbiology

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Bacteroides fragilis, an opportunistic pathogen of humans, is a leading cause of bacteraemias and anaerobic abscesses which are often treated with metronidazole, a drug which damages DNA. This study investigated the responses of the B. fragilis recA three gene operon to the stress experienced during metronidazole treatment and exposure to reactive oxygen species simulating those generated by the host immune system during infection. A transcriptionally regulated response was observed using quantitative RT-PCR after metronidazole and hydrogen peroxide treatment, with all three genes being upregulated under stress conditions. In vivo and in vitro analysis of the functional role of the second gene of the operon was done using heterologous complementation and protein expression (in Escherichia coli), with subsequent biochemical assay. This gene encoded a functional bacterioferritin co-migratory protein (BCP) which was thiol-specific and had antioxidant properties, including protection of the glutamine synthetase III enzyme. This in vitro data supports the hypothesis that the genes of the operon may be involved in protection of the bacteria from the oxidative burst during tissue invasion and may play a significant role in bacterial survival and metronidazole resistance during treatment of B. fragilis infections.

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Rv3134c/devR/devS operon of Mycobacterium bovis BCG is differentially transcribed under “in vitro” stress conditions

Cited by 9 publications

References 36 publications

Global Adaptation to a Lipid Environment Triggers the Dormancy-Related Phenotype of Mycobacterium tuberculosis

Global Adaptation to a Lipid Environment Triggers the Dormancy-Related Phenotype of Mycobacterium tuberculosis

Three Mycobacterium tuberculosis Rel Toxin-Antitoxin Modules Inhibit Mycobacterial Growth and Are Expressed in Infected Human Macrophages

The recA operon: A novel stress response gene cluster in Bacteroides fragilis

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