MTB-Serial-Isolates
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ABSTRACT:
PROVIDER: PRJEB13325 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genomic comparisons among different lineages Mtb isolates.
2010-08-01 | GSE20917 | GEO
Project description:The identification of multidrug resistant (MDR), extensively and totally drug resistant Mycobacterium tuberculosis (Mtb), in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS) compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS) at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S) microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB), cell wall biosynthesis (emb genes), protein synthesis (rpl) and additional central metabolic pathways (ppdK, pknH, pfkB) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB) in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-134]
2013-04-24 | E-BUGS-134 | biostudies-arrayexpress
Project description:Bacterial persister cells are phenotypic variants of regular cells that are tolerant to antibiotics. Analysis of clinical isolates of M. tuberculosis showed that strains vary substantially in their tolerance to antibiotics. The level of persisters was very high is some isolates, suggesting that these are hip mutants. We investigated gene expression differences in eight clinical isolates, four of which we characterized as high-persister strains and four as low-persister, or regular, strains. Comparison of gene expression patterns may provide clues as to the genetic mechanisms underlying persister formation.
2015-01-01 | GSE62025 | GEO
Project description:Heterogeneity of host cells as well as bacteria residing within them has been known to induce drug tolerance in pathogens. In Mycobacterium tuberculosis, particularly, drug tolerance within host is a major hurdle in the path to attain a sterlising cure. Reports have shown how residence of Mtb within macrophages makes the pathogen refractory to anti-TB therapy. However, the mechanisms responsible for induction of tolerance to antibiotics, particularly in resting macrophages where Mtb continues to actively replicate, is yet to be deciphered. Reports have suggested that heterogeneity induced in Mtb by cues sensed in the host environment could be a contributing factor to drug tolerance. With regard to this, differences in redox physiology of intra-macrophage Mtb (mid-point potential of the major cytosolic redox buffer in Mtb, mycothiol- EMSH) have been shown to play a role in influencing antibiotic-mediated killing. In this study, we have attempted to analyse the trascriptomic profiles of individual redox sub-populations of Mtb from within macrophages- viz., the EMSH-reduced bacteria with mid-point potential ranging between -285 and -310 mV, shown to be most refractory to killing by front-line anti-TB antibiotics inside macrophages, as well as EMSH-basal bacteria with mid-point potential ranging between -270 and -280 mV, with a much higher degree of antibiotic susceptibility within macrophages. Analysing gene expression level differences between these bacterial sub-populations would help in providing a mechanistic understanding of drug tolerance in Mtb, bred from phenotypic heterogeneity in the pathogen.
2019-09-13 | GSE123267 | GEO
Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection. Mice were infected with Mtb and treatment with PZA was started at 28 days post-infection. At 42 days and 63 days post-infection, group of animals were euthanized and lung tissue was collected to isolate total RNA and used in microarray experiments. Mtb-infected, untreated animals served as controls.
2013-06-28 | E-GEOD-48027 | biostudies-arrayexpress
Project description:Tuberculosis kills nearly 2 million people through out the world, every year. The outcome of M. tuberculosis infection is determined by the host and bacterial factors. A strong host immune response controls the growth of the bacilli effectively. However, in a host with suboptimal immune response, the bacilli grows and mounts disease. Activation of immune response following M. tuberculosis infection affects the expression of many host genes that are involved in the production of immune system molecules such as cytokines, chemokines, surface receptors and transcriptional regulators that manifest in the change of subsequent cellular events, including chemotaxis and proliferation of effector cells. The infecting bacilli counteracts the bactericidal activities of the host immune cells, primarily by modifying their gene expression. However, the specific nature of the host-pathogen interactions and the outcome of Mtb infection are not fully understood. Tumor necrosis factor-alpha (TNF-a), produced by the immune cells, is an important cytokine in protecting the host against Mtb infection. However, excessive TNF-a production leads to severe inflammation and host cell destruction. In fact, pharmacologic inhibition of TNF-a production has been considered as a therapeutic modality in inflammatory diseases. Interestingly, inhibitors of host phosphodiesterase-4 (PDE4) have been shown to reduce TNF-a production and dampen inflammation without complete immune suppression of the host. In this study, we have explored the use of one of the PDE4 inhibitors, CC-3052, as an adjunct immune modulatory drug, in combination with isoniazid (INH) treatment in rabbit pulmonary tuberculosis. We hypothesize that reducing TNF-a levels during Mtb infection would reduce the environmental pressure on the bacteria, rendering them more amenable to killing by INH. Mtb infected rabbits were treated with CC-3052 or INH or both and the lung tissue were harvested after 4 and 8 weeks of treatment. Lung bacterial load, histologic changes and host and bacterial gene expression were determined for each timepoint and compared between various treatment groups. The results of our study provides data to support the idea that combining anti-TB drugs with an adjunctive immune modulator may enhance the efficacy of current TB therapy regimens and shorten the duration of treatment if applied appropriately to humans. The microarray experiments involves 2 comparison groups. 1) Changes in rabbit gene expression between Mtb infected and uninfected animals; 2). Changes in rabbit gene expression between CC-3052 treated and untreated animals during Mtb infection at 4,8 and 12 weeks post infection. New Zealand White rabbits were infected with Mtb HN878 at 3.2log10 (on day 0). At 4 weeks post infection, one group of infected rabbits were treated with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, and the treatment was continued up to 12 weeks post infection. The compound was used at 25mg/kg body weight, dissolved in distilled water and administered through gavage five days a weeks. Lung tissue from Uninfected, Mtb-infected and Untreated or CC-3052 treated rabbits were isolated at Day0, 4,8 and 12 weeks post infection and used for total RNA extraction. Only the 8 and 12 week timepoints correspond to the associated publication.
2011-03-16 | E-GEOD-27992 | biostudies-arrayexpress
Project description:Respiratory ATP-synthesis is at present the only known mechanism for ATP synthesis in Mtb. This makes Mtb particularly vulnerable to inhibition of respiratory ATP synthase inhibitors such as TMC207, a novel compound for treatment of tuberculosis. We now provide first evidence that Mtb possesses a pathway that is fermentative in nature that could compensate lack of respiratory ATP synthesis. We identified acetate as a fermentation product in Mtb. Production of acetate was mediated by phosphotransacetylase (Pta) and acetate kinase (AckA). In acetate fermenting Mtb cultures, ATP levels remained stable despite inhibition of respiratory ATP synthase. Deletion of the PtaAckA pathway in Mtb decreased ATP content and impaired survival. This study provides evidence that in Mtb substrate level phosphorylation can compensate lack of oxidative phosphorylation, and thus facilitates survival of Mtb in the absence of respiration. Acetate fermentation contributes to adaptation to respiration-limiting conditions, and plays an important role in the emerging field of fermentative metabolism of Mtb. We performed DNA microarray analysis to validate the reduction of oxygen concentration by comparing aerobic and hypoxic cultures. RNA was prepared from Mtb after two days of cultivation in aerobic and in hypoxic cultures. At each condition, Mtb were cultured in medium supplemented with glycerol and glucose. Labelled cDNA from three independent experiments was subjected to array analysis.
2012-12-31 | E-GEOD-35484 | biostudies-arrayexpress
Project description:Genome-wide expression data can provide important insights into normal and pathological cellular processes. However, the ability to use gene expression data to quantitatively assess the activation state of a given signaling pathway or transcriptional network in a sensitive and specific manner remains an important unmet goal. We now describe a computational algorithm, energy-paired scoring (EPS), that satisfies these criteria by predicting pathway activity using gene-gene interactions within a pathway signature in a manner analogous to the estimation of energy generated by two charged particles, as described by Coulomb’s law. We demonstrate the ability of EPS to: quantitatively assess pathway activation levels in vivo and in vitro; accurately estimate the extent of pathway inhibition achieved by gene knockdown; sensitively detect crosstalk between endogenous signaling pathways in vivo; and accurately identify compounds capable of inhibiting selected signaling pathways. Our findings indicate that EPS can accurately predict pathway activity over a wide dynamic range based upon gene expression data sets derived from multiple profiling platforms, as well as different species, tissues and cell types in both in vitro and in vivo contexts Four timepoints (0h, 24h, 48h and 96h) with 3 replicates per timepoint of doxycycline induction for MTB (Control), MTB/TAN, MTB/TOM and MTB/TWNT1
2013-09-18 | E-GEOD-50969 | biostudies-arrayexpress