Host specificity and pathogenic mycobacteria
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ABSTRACT:
PROVIDER: PRJEB23469 | ENA |
REPOSITORIES: ENA
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Project description:Mycobacteria can synthesize NAD+ using either the de novo biosynthesis pathway or the salvage pathway. The deletion of the three genes involved specifically in the NAD+ de novo biosynthesis pathway in the human pathogen Mycobacterium tuberculosis had no effect on the growth of the strain in vivo. In contrast, the same deletion in the bovine pathogen Mycobacterium bovis resulted in a strain that could not grow in vivo and could only grow in vitro with substantial nicotinamide supplmentation. This striking difference was attributed to the known defect in the nicotinamidase PncA of M. bovis, since introducing the M. tuberculosis pncA gene into the M. bovis strain defective for de novo NAD+ biosynthesis restored growth in vitro and in vivo. This study demonstrates that NAD+ starvation is a cidal event in mycobacteria and confirms that enzymes common to the de novo and salvage pathways may be good drug targets. We also propose that simultaneously targeting both the salvage and the de novo NAD+ biosynthesis pathways represents a potentially effective way to treat infection with tubercle bacilli. To characterize the lethality induced by nicotinamide starvation transcriptional profiling of the auxotrophs was performed. Triplicate 50 mL cultures of M. tuberculosis and M. bovis Delta nadABC mutants were grown in 7H9 OADC glycerol 0.05% tween broth in 500 mL roller bottles to an OD600nm= 0.1 in a roller incubator at 37°C. The cells were washed 1x in PBS and resuspended in 50 mL 7H9 OADC glycerol 0.05% tween broth with or without 20mg/L nicotinamide and returned to the incubator. After 7 days, cultures were harvested. Three biological replicates of each of two species with one dye-flip each
2010-05-14 | E-GEOD-18909 | biostudies-arrayexpress
Project description:Mycobacteria can synthesize NAD+ using either the de novo biosynthesis pathway or the salvage pathway. The deletion of the three genes involved specifically in the NAD+ de novo biosynthesis pathway in the human pathogen Mycobacterium tuberculosis had no effect on the growth of the strain in vivo. In contrast, the same deletion in the bovine pathogen Mycobacterium bovis resulted in a strain that could not grow in vivo and could only grow in vitro with substantial nicotinamide supplmentation. This striking difference was attributed to the known defect in the nicotinamidase PncA of M. bovis, since introducing the M. tuberculosis pncA gene into the M. bovis strain defective for de novo NAD+ biosynthesis restored growth in vitro and in vivo. This study demonstrates that NAD+ starvation is a cidal event in mycobacteria and confirms that enzymes common to the de novo and salvage pathways may be good drug targets. We also propose that simultaneously targeting both the salvage and the de novo NAD+ biosynthesis pathways represents a potentially effective way to treat infection with tubercle bacilli. To characterize the lethality induced by nicotinamide starvation transcriptional profiling of the auxotrophs was performed. Triplicate 50 mL cultures of M. tuberculosis and M. bovis Delta nadABC mutants were grown in 7H9 OADC glycerol 0.05% tween broth in 500 mL roller bottles to an OD600nm= 0.1 in a roller incubator at 37°C. The cells were washed 1x in PBS and resuspended in 50 mL 7H9 OADC glycerol 0.05% tween broth with or without 20mg/L nicotinamide and returned to the incubator. After 7 days, cultures were harvested.
2010-02-24 | GSE18909 | GEO
Project description:Two selected compounds, 2,4-disubstituted pyridine derivatives (11 and 15), revealed significant bactericidal activity against Mycobacterium tuberculosis deposited within human macrophages as well as against biofilm-forming tubercle bacilli. The mass spectrometry-based proteomics (LC-MS/MS) of the wild-type tubercle bacilli growing in the subinhibitory concentration of 11 or 15 revealed 15 overproduced proteins not detectable in the control cells including virulence-related proteins.
2022-11-02 | PXD035807 | Pride
Project description:Rationale: Tuberculosis has a devastating impact on global health by claiming nearly 1.4 million lives each year. During infection Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, produces heterogenous populations some of which don’t produce colonies on agar but grow in liquid media and often require supplementation with culture supernatants or recombinant Resuscitation-promoting factor, thus defined as differentially culturable bacilli. Objectives: to evaluate whether exposure to nitric oxide (NO), a well-known host defence molecule, alters mycobacterial growth phenotypes and drives generation of Rpf-dependent differentially culturable bacilli. Methods: a novel NO donor was synthesised and tested against Mtb and Mycobacterium bovis BCG in vitro, followed by growth assays, flow cytometry analysis and assessment of transcriptomic responses. Resuscitation-promoting factor (Rpf) inhibitors were used to characterise the role of Rpf proteins in the reactivation of NO-treated mycobacteria. Mycobacterial phenotypes were also investigated during infection of THP-1 macrophages activated with retinoic acid and vitamin D3. Measurements and Main Results: differentially culturable mycobacteria were generated after exposure to the novel NO donor or during infection of activated THP-1 cells. Resuscitation of these differentially culturable bacilli was largely abolished by specific Rpf inhibitors. Transcriptomic analysis revealed redox-associated stress signatures mediated by SigH and SigF, with significant down-regulation of ribosome and cell wall architecture genes, including rpfA, rpfB and rpfE, and induction of genes involved in response to thiol stress, sulphur metabolism and iron acquisition. Conclusion: Our study provides mechanistic insights into the generation of Rpf-dependent Mtb during tuberculosis and outlines a critical role of NO in this process.
2023-09-01 | E-MTAB-10776 | biostudies-arrayexpress
Project description:We analyzed the genes expressed, or the transcriptome, of bacilli Mycobacterium bovis BCG Pasteur (wtBCG) and a mutant strain obtained by transposition of the gene BCG_ BCG_2177c (mtBCG), cultured in the presence of a lipid mixture (fatty acids/cholesterol) as main carbon source. Using RNAseq we identified a group of genes that provides novel insight regarding the metabolic pathways and transcriptional regulation, and pathogenic features that were influenced by BCG_2177c gene, a TetR-like repressor, during the lipid metabolism in slow-growing mycobacteria that could be extrapolated to other members of the MTBC.
2022-06-20 | GSE175579 | GEO
Project description:Anaplasma and Mycobacterium species are known to modify gene expression in ruminants. The objectives of this study were (a) to characterize global gene expression profiles in European red deer (Cervus elaphus) in response to Anaplasma ovis and A. ovis/Mycobacterium bovis/M. avium sub. paratuberculosis (MAP) infections, (b) to compare the expression of immune response genes between A. ovis- and A. ovis/M. bovis/MAP-infected deer, and (c) to characterize the differential expression of immune response genes identified in red deer in cattle infected with M. bovis and A. marginale. The results of this study showed that global gene differential expression in A. ovis- and A. ovis/M. bovis/MAP-infected deer results in the modification of common and pathogen-specific cellular biological processes. The differential expression of host immune response genes also showed pathogen-specific signatures and the effect of infection with multiple pathogens on red deer host immune response. These results suggested that intracellular bacteria from Anaplasma and Mycobacterium genera use similar mechanisms to infect and multiply within ruminant host cells while pathogen-specific mechanisms underline differences that could contribute to disease characterization and diagnosis in ruminants.
2010-12-31 | GSE21967 | GEO
Project description:Anaplasma and Mycobacterium species are known to modify gene expression in ruminants. The objectives of this study were (a) to characterize global gene expression profiles in European red deer (Cervus elaphus) in response to Anaplasma ovis and A. ovis/Mycobacterium bovis/M. avium sub. paratuberculosis (MAP) infections, (b) to compare the expression of immune response genes between A. ovis- and A. ovis/M. bovis/MAP-infected deer, and (c) to characterize the differential expression of immune response genes identified in red deer in cattle infected with M. bovis and A. marginale. The results of this study showed that global gene differential expression in A. ovis- and A. ovis/M. bovis/MAP-infected deer results in the modification of common and pathogen-specific cellular biological processes. The differential expression of host immune response genes also showed pathogen-specific signatures and the effect of infection with multiple pathogens on red deer host immune response. These results suggested that intracellular bacteria from Anaplasma and Mycobacterium genera use similar mechanisms to infect and multiply within ruminant host cells while pathogen-specific mechanisms underline differences that could contribute to disease characterization and diagnosis in ruminants. A gene expression pre analysis was made in deers naturally infected with Anaplasma ovis and Mycobacterium complex using Affymetrix Bos taurus microarray to detect differentialy expressed genes. The immune response genes with variation in expression were analyzed by real time RT-PCR in the same samples and a bigger group of deers. A real time RT-PCR analysis was also made in Bos taurus naturally infected with Anaplasma marignale.
2010-12-31 | E-GEOD-21967 | biostudies-arrayexpress
Project description:Mycobacterium avium is the most common nontuberculous mycobacterium (NTM) species causing infectious disease. Here, we characterized a M. avium infection model in zebrafish larvae, and compared it to M. marinum infection, a model of tuberculosis. Using RNAseq analysis, we found a distinct transcriptome response in cytokine-cytokine receptor interaction for M. avium and M. marinum infection. In addition, we found substantial differences in gene expression in metabolic pathways, phagosome formation, matrix remodeling, and apoptosis in response to these mycobacterial infections.
2023-01-12 | GSE218892 | GEO
Project description:Global gene expression analysis of Mycobacterium bovis BCG following Triclosan treatment using Affymetrix GeneChip arrays. Results from this study provide insight into the molecular mechanisms underlying the cellular response of Mycobacterium bovis BCG to Triclosan
2012-12-25 | GSE33800 | GEO
Project description:Mycobacterium tuberculosis infects a third of the world's population. Primary tuberculosis involving active fast bacterial replication is often followed by asymptomatic latent tuberculosis, which is characterised by slow or non-replicating bacteria. Reactivation of the latent infection involving a switch back to active bacterial replication can lead to post-primary transmissible tuberculosis. Mycobacterial mechanisms involved in slow growth or switching growth rate provide rational targets for the development of new drugs against persistent mycobacterial infection. Using chemostat culture to control growth rate we screened a transposon mutant library by Transposon site hybridization (TraSH) selection to define the genetic requirements for slow and fast growth of Mycobacterium bovis (BCG) and for the requirements of switching growth rate. We identified 84 genes that are exclusively required for slow growth (69 hours doubling time) and 256 genes required for switching from slow to fast growth. To validate these findings we performed experiments using individual M. tuberculosis and M. bovis BCG knock out mutants. We have demonstrated that growth rate control is a carefully orchestrated process which requires a distinct set of genes encoding several virulence determinants, gene regulators and metabolic enzymes. The mce1 locus appears to be a component of the switch to slow growth rate, which is consistent with the proposed role in virulence of M. tuberculosis. These results suggest novel perspectives for unravelling the mechanisms involved in the switch between acute and persistent TB infections and provide a means to study aspects of this important phenomenon in vitro. Data is also available from http://bugs.sgul.ac.uk/E-BUGS-83
2009-04-28 | E-BUGS-83 | biostudies-arrayexpress