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In vitro dormancy achieved by multiple stresses in Mycobacterium tuberculosis

ABSTRACT: The human pathogen, Mycobacterium tuberculosis, develops a dormant infection, in which organisms survive within the body. We established a unique in vitro dormancy model based on the characterization of drug-resistance to INH and rifampin. M. tuberculosis cells were maintained in controlled and defined multiple stress conditions with low oxygen (5% dissolved oxygen tension), acid (pH 5.) along with glycerol-deprived medium conditions. To monitor gene expression changes in M. tuberculosis in response to the multiple stresses, we performed microarray analysis at the time point of 1, 2, 3, 6, and 12days after treatment. M. tuberculosis adapting to multiple stresses displayed characteristics associated with persistence in vivo, including entry into a non-replicative state and the repression of genes involved in energy regeneration. Under in vitro multiple-stresses, M. tuberculosis significantly modulated gene expression mainly in response to the starvation stresses. Cells exposed to these multiple stress conditions shows significant drug-resistance. Comparison with other in vivo expression profiles demonstrates induction of several common genes for in vitro dormancy conditions. Keywords: Stress response in time course.

ORGANISM(S): Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv

PROVIDER: GSE10391 | GEO | 2008/05/01

SECONDARY ACCESSION(S): PRJNA108139

REPOSITORIES: GEO

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In vitro dormancy achieved by multiple stresses in Mycobacterium tuberculosis

Project description:The human pathogen, Mycobacterium tuberculosis, develops a dormant infection, in which organisms survive within the body. We established a unique in vitro dormancy model based on the characterization of drug-resistance to INH and rifampin. M. tuberculosis cells were maintained in controlled and defined multiple stress conditions with low oxygen (5% dissolved oxygen tension), acid (pH 5.) along with glycerol-deprived medium conditions. To monitor gene expression changes in M. tuberculosis in response to the multiple stresses, we performed microarray analysis at the time point of 1, 2, 3, 6, and 12days after treatment. M. tuberculosis adapting to multiple stresses displayed characteristics associated with persistence in vivo, including entry into a non-replicative state and the repression of genes involved in energy regeneration. Under in vitro multiple-stresses, M. tuberculosis significantly modulated gene expression mainly in response to the starvation stresses. Cells exposed to these multiple stress conditions shows significant drug-resistance. Comparison with other in vivo expression profiles demonstrates induction of several common genes for in vitro dormancy conditions. Keywords: Stress response in time course. Samples under multiple stress condition were taken at day 1, 2, 3, 6, and 12 for microarray hybridization. More than two technical replicates per biological samples with Cy3/5 dye-swaps.

2008-05-01 | E-GEOD-10391 | biostudies-arrayexpress

Mycobacterium tuberculosis H37Rv

Project description:In vitro dormancy achieved by multiple stresses in Mycobacterium tuberculosis

| PRJNA108139 | ENA

Effect of INH treatment on Mycobacterium tuberculosis gene expression in various dormancy models.

Project description:These data represent the expression patterns of Mycobacterium tuberculosis in progressive hypoxia, nutrient depletion, and in-vivo hollow fiber models of dormancy. The assumptions are that the set of genes that respond to INH treatment during Log phase growth would not be differentially regulated during INH treatment in the dormancy models, and that the overall number of differentially regulated genes would be reduced do to the low metabolic state of the cells. Keywords: Dormancy Model Drug Response Comparison

2007-12-14 | GSE9776 | GEO

TCA1 Stimulon in Mycobacterium tuberculosis

Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1M-bM-^@M-^Ys activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs. Transcriptional profile of TCA1-treated cells relative to DMSO-treated control. Three biological replicates, third is a dye flip.

2013-05-24 | E-GEOD-42151 | biostudies-arrayexpress

TCA1 Stimulon in Mycobacterium tuberculosis

Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1’s activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs.

2013-05-24 | GSE42151 | GEO

Profiling the proteome of Mycobacterium tuberculosis during dormancy and reactivation

Project description:Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and to get reactivated later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating bacteria that were made dormant employing Wayne’s dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free one-dimensional LC/MS/MS analysis.

2015-06-01 | PXD001158 | Pride

Proteomic Analysis of Drug-resistant Mycobacteria

Project description:Tuberculosis, caused by the pathogen Mycobacterium tuberculosis is a worldwide public health threat. Mycobacterium tuberculosis is capable of resisting of various stresses in host cells including high levels of ROS and copper ions. To better understand the resistance mechanisms of mycobacteria to copper, we generated a copper-resistant strain of Mycobacterium smegmatis, mc2155-Cu from the selection of copper sulfate treated-bacteria. The mc2155-Cu strain has the 5-fold higher resistance to copper sulfate and the 2-fold higher resistance to isoniazid (INH) than its parental strain mc2155, respectively. Quantitative proteomics was carried out to find differentially expressed proteins between mc2155 and mc2155-Cu. Among 345 differentially expressed proteins, copper-translocating P-type ATPase was up-regulated, while all other ABC transporters were down-regulated in mc2155-Cu, suggesting copper-translocating P-type ATPase plays a crucial role in copper resistance. Results also indicated that the down-regulation of metabolic enzymes and decreases in cellular NAD, FAD, mycothiol, and glutamine levels in mc2155-Cu were responsible to its slow growth rate as compared to mc2155. Down-regulation of KatG2 expression in both protein and mRNA levels indicates the co-evolution of copper and INH resistance in copper resistance bacteria, and provides new evidences to understanding of the molecular mechanisms of survival of mycobacteria under stress conditions.

2016-04-13 | PXD001989 | Pride

Mycobacterium tuberculosis Lsr2 is a global transcriptional regulator required for adaptation to changing oxygen levels and virulence

Project description:To survive a dynamic host environment, Mycobacterium tuberculosis must endure a series of challenges from reactive oxygen and nitrogen stress, to drastic shifts in oxygen availability. The mycobacterial Lsr2 protein has been implicated in reactive oxygen defense via direct protection of DNA. To examine the role of Lsr2 in pathogenesis and physiology of M. tuberculosis, we generated a strain deleted for lsr2. Analysis of the M. tuberculosis ?lsr2 strain demonstrated that Lsr2 is not required for DNA protection, as this strain was as equally susceptible as the wild-type to DNA-damaging agents. The lsr2 mutant did display severe growth defects under normoxic and hyperoxic conditions, but was not required for growth under low oxygen conditions. However, it was also required for adaptation to anaerobiosis. The defect in anaerobic adaptation led to a marked decrease in viability during, as well as a lag in recovery from, anaerobiosis. Gene expression profiling of ?lsr2 under aerobic and anaerobic conditions in conjunction with published DNA binding-site data indicate that Lsr2 is a global transcriptional regulator controlling adaptation to changing oxygen levels. The ?lsr2 strain was capable of establishing an early infection in the Balb/c mouse model; however, it was severely defective in persisting in the lungs and caused no discernible lung pathology. These findings demonstrate M. tuberculosis Lsr2 is a global transcriptional regulator required for control of genes involved in adaptation to extremes in oxygen availability and is required for persistent infection. Wild type H37Rv or lsr2 mutant strains were grown aerobically or in a Rach dormancy model in dubos tween albumin media and analyzed. Alternately, either aerobically grown or Rach model hypoxic samples were challenged with H2O2 samples and harvested 1h later. Experiments were repeated in triplicate or quadruplicate.

2014-05-24 | E-GEOD-57948 | biostudies-arrayexpress

Comparative label-free lipidomic analysis of Mycobacterium tuberculosis during dormancy and reactivation

Project description:Mycobacterium tuberculosis employs several strategies to combat and adapt to adverse conditions encountered inside the host. The non-replicative dormant state of the bacterium is linked to drug resistance and slower response to anti-tubercular therapy. It is known that alterations in lipid content allow dormant bacteria to acclimatize to cellular stress. Employing comparative lipidomic analysis we profiled the changes in lipid metabolism in M. tuberculosis using a modified Wayne's model of hypoxia-induced dormancy. Further we subjected the dormant bacteria to resuscitation, and analyzed their lipidomes until the lipid profile was similar to that of normoxially grown bacteria. An enhanced degradation of cell wall-associated and cytoplasmic lipids during dormancy, and their gradual restoration during reactivation, were clearly evident. This study throws light on distinct lipid metabolic patterns that M. tuberculosis undergoes to maintain its cellular energetics during dormancy and reactivation.

2018-10-22 | MTBLS304 | MetaboLights

Examining the basis of isoniazid tolerance in nonreplicating Mycobacterium tuberculosis using transcriptional profiling

Project description:Background: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. Results: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. Conclusion: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance. Data is also available from <ahref=http://bugs.sgul.ac.uk/E-BUGS-104 target=_blank>BuG@Sbase</a>

2011-01-17 | E-BUGS-104 | biostudies-arrayexpress

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