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  PE_PGRS18/RV0980C is profiled in 28 experiments

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Unique roles of DosT and DosS in DosR regulon induction and Mycobacterium tuberculosis dormancy.

Honaker RW, et al. (2009) Infect Immun 77(8):3258-63

In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, which is important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors have been postulated biochemically, but their roles in vivo have remained unclear. Various DosS and DosT mutant strains were analyzed ... Expand against wild type (reference strain H37Rv, identical conditions as mutant) under various conditions: day 6 in an anaerobic dormancy model, 4 or 24 hours in a GasPak model, or log phase with the addition of a nitric oxide donor. Experiments were repeated in triplicate or quadruplicate. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild-type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild-type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state. Hide text

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Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha -crystallin.

Sherman DR, et al. (2001) Proc Natl Acad Sci U S A 98(13):7534-9

Unlike many pathogens that are overtly toxic to their hosts, the primary virulence determinant of Mycobacterium tuberculosis appears to be its ability to persist for years or decades within humans in a clinically latent state. Since early in the 20th century latency has been linked to hypoxic conditions within the host, but the response of M. tuberculosis to a hypoxic signal remains poorly characterized. The M. ... Expand tuberculosis alpha-crystallin (acr) gene is powerfully and rapidly induced at reduced oxygen tensions, providing us with a means to identify regulators of the hypoxic response. Using a whole genome microarray, we identified >100 genes whose expression is rapidly altered by defined hypoxic conditions. Numerous genes involved in biosynthesis and aerobic metabolism are repressed, whereas a high proportion of the induced genes have no known function. Among the induced genes is an apparent operon that includes the putative two-component response regulator pair Rv3133cy Rv3132c. When we interrupted expression of this operon by targeted disruption of the upstream gene Rv3134c, the hypoxic regulation of acr was eliminated. These results suggest a possible role for Rv3132cy3133cy3134c in mycobacterial latency. Hide text

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The response of mycobacterium tuberculosis to reactive oxygen and nitrogen species.

Voskuil MI, et al. (2011) Front Microbiol 2():105

The bacteriostatic and bactericidal effects and the corresponding expression profiles of Mycobacterium tuberculosis to representative oxidative and nitrosative stresses were investigated by growth and survival studies and whole genome expression analysis. The response of M. tuberculosis to a range of hydrogen peroxide (H2O2) concentrations tended to fall into three distinct categories: (1) low level exposure ... Expand resulted in induction of few H2O2 sensitive genes, (2) intermediate exposure resulted in massive transcriptional changes without an effect on growth or survival, and (3) high exposure resulted in a muted transcriptional response and eventual death. Nitric oxide (NO) exposure initiated much of the same transcriptional response as H2O2. However, unlike H2O2 exposure, NO exposure affected a dose-dependent bacteriostatic activity without killing and induction of dormancy-related genes. Included in the shared response to H2O2 and NO was the induction of genes encoding oxidative stress detoxification and iron-sulfur cluster repair functions. Expression of several key oxidative stress defense genes was constitutive, or increased moderately from an already elevated level, suggesting bacilli that are continually primed for oxidative stress defense. Deletion of the known oxidative stress responsive regulator, FurA, resulted in the constitutive expression of furA, katG, and Rv1907c; while other genes do not appear to be solely controlled by FurA. In contrast to Escherichia coli, M. tuberculosis appears highly resistant to DNA damage-dependent killing caused by low mill molar levels of H2O2. Furthermore, instead of limiting access to iron to prevent hydroxyl radical formation from H2O2 and thus DNA damage, M. tuberculosis induced iron uptake genes in response to H2O2 and NO. Hide text

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Ancestral antibiotic resistance in Mycobacterium tuberculosis.

Morris RP, et al. (2005) Proc Natl Acad Sci U S A 102(34):12200-5

Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium tuberculosis to the majority of clinically applied antibiotics. Such resistance is partially provided by the low permeability of their unique cell envelope. Here we describe a complementary system that coordinates resistance to drugs that have penetrated the envelope, allowing mycobacteria to tolerate ... Expand diverse classes of antibiotics that inhibit cytoplasmic targets. This system depends on whiB7, a gene that pathogenic Mycobacterium shares with Streptomyces, a phylogenetically related genus known as the source of diverse antibiotics. In M. tuberculosis, whiB7 is induced by subinhibitory concentrations of antibiotics (erythromycin, tetracycline, and streptomycin) and whiB7 null mutants (Streptomyces and Mycobacterium) are hypersusceptible to antibiotics in vitro. M. tuberculosis is also antibiotic sensitive within a monocyte model system. In addition to antibiotics, whiB7 is induced by exposure to fatty acids that pathogenic Mycobacterium species may accumulate internally or encounter within eukaryotic hosts during infection. Gene expression profiling analyses demonstrate that whiB7 transcription determines drug resistance by activating expression of a regulon including genes involved in ribosomal protection and antibiotic efflux. Components of the whiB7 system may serve as attractive targets for the identification of inhibitors that render M. tuberculosis or multidrug-resistant derivatives more antibiotic-sensitive. Hide text

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Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis.

Park HD, et al. (2003) Mol Microbiol 48(3):833-43

Unlike many pathogens that are overtly harmful to their hosts, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. Latency is often linked to hypoxic conditions within the host. Among M. tuberculosis genes induced by hypoxia is a putative transcription factor, Rv3133c/DosR. We performed targeted disruption of this locus followed by transcriptome analysis of wild-type and ... Expand mutant bacilli. Nearly all the genes powerfully regulated by hypoxia require Rv3133c/DosR for their induction. Computer analysis identified a consensus motif, a variant of which is located upstream of nearly all M. tuberculosis genes rapidly induced by hypoxia. Further, Rv3133c/DosR binds to the two copies of this motif upstream of the hypoxic response gene alpha-crystallin. Mutations within the binding sites abolish both Rv3133c/DosR binding as well as hypoxic induction of a downstream reporter gene. Also, mutation experiments with Rv3133c/DosR confirmed sequence-based predictions that the C-terminus is responsible for DNA binding and that the aspartate at position 54 is essential for function. Together, these results demonstrate that Rv3133c/DosR is a transcription factor of the two-component response regulator class, and that it is the primary mediator of a hypoxic signal within M. tuberculosis. Hide text

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Cell population heterogeneity in Mycobacterium tuberculosis H37Rv.

Andreu N and Gibert I (2008) Tuberculosis (Edinb) 88(6):553-9

The laboratory strain H37Rv represents one of the most commonly used strains in the study of Mycobacterium tuberculosis. Despite the apparent stability of the strain, the absence of a selective pressure for virulence factors could lead to the in vitro accumulation of attenuated mutants. To assess this hypothesis, we performed a systematic analysis of individual clones isolated from subcultured M. tuberculosis H37Rv ... Expand and from a non-subcultured frozen stock. First, we studied two virulence indicators: neutral red staining and content of phthiocerol dimycocerosates (PDIMs). We found that H37Rv formed a mixed population containing wild-type cells, as well as neutral red and PDIM mutants. Then, we compared the global gene expression of 3 isolated clones (which displayed various phenotypes) and the non-subcultured stock, by microarray analysis. This transcriptional profiling confirmed that a significant heterogeneity existed despite, and in addition to, the neutral red and PDIM phenotypes. These results strongly suggest that great caution must be taken in extrapolating data obtained with M. tuberculosis H37Rv grown in vitro, and it would be prudent to study several independent clones to obtain valid conclusions. For this purpose, the neutral red and PDIM phenotypes might be useful indicators of undesired heterogeneity. Hide text

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Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy.

Voskuil MI, et al. (2004) Tuberculosis (Edinb) 84(3-4):218-27

The innate mechanisms used by Mycobacterium tuberculosis to persist during periods of non-proliferation are central to understanding the physiology of the bacilli during latent disease. We have used whole genome expression profiling to expose adaptive mechanisms initiated by M. tuberculosis in two common models of M. tuberculosis non-proliferation. The first of these models was a standard growth curve in which gene ... Expand expression changes were followed from exponential growth through the transition to stationary phase. In the second model, we followed the adaptive process of M. tuberculosis during transition from aerobic growth to a state of anaerobic non-replicating persistence. The most striking finding from these experiments was the strong induction of the entire DosR "dormancy" regulon over approximately 20 days during the long transition to an anaerobic state. This is contrasted by the muted overall response to aerated stationary phase with only a partial dormancy regulon response. From the results presented here we conclude that the respiration-limited environment of the oxygen-depleted NRP model recreates at least one fundamental factor for which the genome of M. tuberculosis encodes a decisive adaptive program. Hide text

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DosR-regulon genes induction in Mycobacterium bovis BCG under aerobic conditions.

Flores Valdez MA and Schoolnik GK (2010) Tuberculosis (Edinb) 90(3):197-200

In this report we demonstrated that under aerobic conditions, Mycobacterium bovis BCG expressing an hsp60-driven second copy of the hypoxia-related transcriptional regulator DosR increased 2-fold or greater the expression of 38 out of the 48 genes belonging to the DosR regulon, including the latency antigens Rv1733c, Rv2029, Rv2627, and Rv2628. Expression of DosR under these conditions slightly delayed in vitro ... Expand growth, but did not promote a non-replicating state as opposed to microaerobic and hypoxic adaptation. Our results suggest BCG producing DosR can be cultured under standard in vitro conditions, allowing evaluation of this strain as a latency-specific vaccine candidate. PMID: 20421176 Hide text

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Comparative expression studies of a complex phenotype: cord formation in Mycobacterium tuberculosis.

Gao Q, et al. (2004) Tuberculosis (Edinb) 84(3-4):188-96

The aggregation of mycobacteria into structures known as cords is an intrinsic property of the human tubercle bacillus. This property is thought to be determined by the lipid composition of the bacterial cell surface and may contribute to the virulence of the organism. Using microarray technology, we compared the pattern of gene expression of H37Rv, a virulent, cording strain of Mycobacterium tuberculosis, with ... Expand H37Ra, an avirulent, non-cording strain derived from the same original patient isolate, under five different nutrient combinations and growth conditions. Under all of these conditions, H37Rv formed cords and H37Ra did not. By focusing our analysis only on genes that were differentially expressed under all conditions, we hoped to enrich the resulting gene list for genes associated with cording. We identified 22 genes that were consistently expressed at higher levels in H37Rv than in H37Ra under all conditions tested. Genes involved in lipid metabolism and the cell membrane were significantly enriched in our gene list, indicating that the cell wall and the cell membrane may be the major sites of difference between these two strains. This work represents a new strategy for enriching gene lists for relevant genes, which may also be applicable for other types of problems. Hide text

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PepD participates in the mycobacterial stress response mediated through MprAB and SigE.

White MJ, et al. (2010) J Bacteriol 192(6):1498-510

The researchers compare total RNA from early log growth cultures of both wild type and PepD null mutant strain using microarray analysis to understand transcriptional profiles in a PepD null mutant ... Expand strain. Hide text

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Transcriptional responses of Mycobacterium tuberculosis to lung surfactant.

Schwab U, et al. (2009) Microb Pathog 46(4):185-93

This study uses microarray analyses to examine gene expression profiles for Mycobacterium tuberculosis (Mtb) induced by exposure in vitro to bovine lung surfactant preparations that vary in apoprotein content: (i) whole lung surfactant (WLS) containing the complete mixture of endogenous lipids and surfactant proteins (SP)-A, -B, -C, and -D; (ii) extracted lung surfactant (CLSE) containing lipids plus SP-B and -C; ... Expand (iii) column-purified surfactant lipids (PPL) containing no apoproteins, and (iv) purified human SP-A. Exposure to WLS evoked a multitude of transcriptional responses in Mtb, with 52 genes up-regulated and 23 genes down-regulated at 30min exposure, plus 146 genes up-regulated and 27 genes down-regulated at 2h. Notably, WLS rapidly induced several membrane-associated lipases that presumptively act on surfactant lipids as substrates, and a large number of genes involved in the synthesis of phthiocerol dimycocerosate (PDIM), a cell wall component known to be important in macrophage interactions and Mtb virulence. Exposure of Mtb to CLSE, PPL, or purified SP-A caused a substantially weaker transcriptional response (<=20 genes were induced) suggesting that interactions among multiple lipid-protein components of WLS may contribute to its effects on Mtb transcription. Hide text

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Mycobacterium tuberculosis modulates its cell surface via an oligopeptide permease (Opp) transport system.

Flores-Valdez MA, et al. (2009) FASEB J 23(12):4091-104

M. tuberculosis strain 1254 wild type (WT) and its isogenic delta Rv3662c-Rv3665c KO (opp KO) and complemented opp::opp were cultured in vitro, in liquid 7H9 media supplemented with OADC and 0.05% Tween 80, 0.5% glycerol, in a 150 mL volume, contained in roller bottles, incubated at 37oC. Growth was monitored as OD600 nm and recorded on a daily basis. In all experiments, the starting OD600 nm was 0.04-0.05. ... Expand Aliquots were removed at each OD600 nm to make serial dilutions, plate onto 7H10 OADC agar plates for CFU counts. When cells reached OD600 nm of 0.3, 1.0, and 1.5, a 10-30 mL aliquot was taken, centrifuged 3 min at 3000 g, at room temperature, and the supernatant was discarded, with cell pellets being immediately frozen by inclusion into dry ice. Frozen cell pellets were stored at -80oC for later RNA isolation. In all experiments, RNA from WT was labeled with Cy5, and RNA from the opp KO was labeled with Cy3. In all experiments, the microarray comparsion used RNA from cells of the same growth stage, i.e., WT OD 0.3 vs opp KO OD 0.3, WT OD 1.0 vs opp KO OD 1.0, and WT OD 1.5 vs opp KO OD 1.5. When comparing the Complemented opp::opp vs the mutant opp KO, RNA from the later strain was Cy3-labeled. Hide text

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NAD+ auxotrophy is bacteriocidal for the tubercle bacilli.

Vilcheze C, et al. (2010) Mol Microbiol 76(2):365-77

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 ... Expand 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 37oC. 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. Hide text

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Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival.

Homolka S, et al. (2010) PLoS Pathog 6(7):e1000988

This study uses microarray analyses to examine baseline gene expression profiles for Mycobacterium tuberculosis complex clinical isolates relative to reference strain CDC1551 during log phase growth in vitro in 7H9 broth. For this in vitro analyses, log-phase mycobacteria in starter cultures grown to mid-log from frozen stocks were inoculated into 7H9-OADC medium in 25-cm2 vented flasks at an OD of ~0.05 and grown ... Expand without shaking for ~1 week to an OD of ~0.5-0.6. Hide text

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Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival.

Homolka S, et al. (2010) PLoS Pathog 6(7):e1000988

This study uses microarray analyses to examine transcriptional responses of Mycobacterium tuberculosis complex clinical isolates to phagosomal cues encountered inside resting murine bone marrow-derived macrophages 24hr post-infection. Transcript levels of intracellular mycobacteria were compared to extracellular bacteria of the same strain (An aliquot of the inoculum used to infect macrophages was incubated in the ... Expand absence of macrophages for 24hr in an identical flask). Hide text

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Bioactive Pyridine-N-oxide Disulfides from Allium stipitatum

O'Donnell G, et al. (2009) J Nat Prod 72(3):360-365

In this study, the researchers isolated a colorless waxy solid from the chloroform extract of Allium stipitatum as Compound 1. They demonstrated compound 1 is a potent bactericidal agent against nonreplicating Mycobacterium tuberculosis. Using microarray technology the authors report gene expression profiles in cells treated with either 2, 5, or 10 ug/ml of compound 1 or an equivalent amount of DMSO as ... Expand control for 6 h. Gene expression studies revealed that transcriptional profiles elicited in response to compound 1 were similar to the profiles generated during treatment of cells with compounds such as menadione and 8-quinolinol that result in oxidative stress. They included the thioredoxin system components encoded by trxB2 and trxC as well as several genes associated with the heat shock response such as clpB, sigH, dnaJ, dnaK, hsp, Rv0331, Rv3463, Rv3054c, and Rv1334-Rv1335. These results suggest that compound 1 possibly generates damaged proteins and other oxidative stress signals as part of its mechanism of action.

The following is the full abstract of this published study.
O'Donnell G, et al. (2009) J Nat Prod 72(3):360-365
From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2'-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide. Compounds 1 and 2 are new natural products, and 3 is reported for the first time from an Allium species. All compounds were evaluated for activity against fast-growing species of Mycobacterium, methicillin-resistant Staphylococcus aureus, and a multidrug-resistant (MDR) variants of S. aureus. Compounds 1 and 2 exhibited minimum inhibitory concentrations (MICs) of 0.5-8 mug/ml against these strains. A small series of analogues of 1 were synthesized in an attempt to optimize antibacterial activity, although the natural product had the most potent in vitro activity. In a whole-cell assay at 30 mug/ml, 1 was shown to give complete inhibition of the incorporation of (14)C-labeled acetate into soluble fatty acids, indicating that it is potentially an inhibitor of fatty acid biosynthesis. In a human cancer cell line antiproliferative assay, 1 and 2 displayed IC(50) values ranging from 0.3 to 1.8 muM with a selectivity index of 2.3 when compared to a human somatic cell line. Compound 1 was evaluated in a microarray analysis that indicated a similar mode of action to menadione and 8-quinolinol by interfering with the thioredoxin system and up-regulating the production of various heat shock proteins. This compound was also assessed in a mouse model for in vivo toxicity. Hide text

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The Mycobacterium tuberculosis ECF sigma factor sigmaE: role in global gene expression and survival in macrophages.

Manganelli R, et al. (2001) Mol Microbiol 41(2):423-37

In previously published work, we identified three Mycobacterium tuberculosis sigma (s) factor genes responding to heat shock (sigB, sigE and sigH ). Two of them (sigB and sigE ) also responded to SDS exposure. As these responses to stress suggested that the s factors encoded by these genes could be involved in pathogenicity, we are studying their role in physiology and virulence. In this work, we characterize a sigE ... Expand mutant of M. tuberculosis H37Rv. The sigE mutant strain was more sensitive than the wild-type strain to heat shock, SDS and various oxidative stresses. It was also defective in the ability to grow inside both human and murine unactivated macrophages and was more sensitive than the wild-type strain to the killing activity of activated murine macrophages. Using microarray technology and quantitative reverse transcription?polymerase chain reaction (RT?PCR), we started to define the sigmaE regulon of M. tuberculosis and its involvement in the global regulation of the stress induced by SDS. We showed the requirement for a functional sigE gene for full expression of sigB and for its induction after SDS exposure but not after heat shock. We also identified several genes that are no longer induced when sigmaE is absent. These genes encode proteins belonging to different classes including transcriptional regulators, enzymes involved in fatty acid degradation and classical heat shock proteins. Hide text

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Role of the extracytoplasmic-function sigma factor sigma(H) in Mycobacterium tuberculosis global gene expression.

Manganelli R, et al. (2002) Mol Microbiol 45(2):365-74

Like other bacterial species, Mycobacterium tuberculosis has multiple sigma (s) factors encoded in its genome. In previously published work, we and others have shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and, in some cases, cause attenuated virulence phenotypes. In this paper, we characterize a M. tuberculosis mutant lacking the ... Expand ECF s factor sigma-H. This mutant was more sensitive than the wild type to heat shock and to various oxidative stresses, but did not show decreased ability to grow inside macrophages. Using quantitative reverse transcription-PCR and microarray technology, we have started to define the sigma-H regulon and its involvement in the global regulation of the response to heat shock and the thiol-specific oxidizing agent diamide. We identified 48 genes whose expression increased after exposure of M. tuberculosis to diamide; out of these, 39 were not induced in the sigH mutant, showing their direct or indirect dependence on sigma-H. Some of these genes encode proteins whose predicted function is related to thiol metabolism, such as thioredoxin, thioredoxin reductase and enzymes involved in cysteine and molybdopterine biosynthesis. Other genes under sigma-H control encode transcriptional regulators such as sigB, sigE, and sigH itself. Hide text

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The three RelE homologs of Mycobacterium tuberculosis have individual, drug-specific effects on bacterial antibiotic tolerance.

Singh R, et al. (2010) J Bacteriol 192(5):1279-91

In Escherichia coli, expression of the RelE and HipA toxins in the absence of their cognate antitoxins has been associated with generating multidrug-tolerant "persisters." The current study is aimed at understanding the mechanism of action of the RelE family of toxins on the metabolism of Mycobacterium tuberculosis. To this effect, toxin expression was induced under the control of a tetracycline regulatable promoter ... Expand and transcriptional profiles compared during overexpression of the three RelE toxin family members, namely RelE1, RelE2 and RelE3. RNA isolated from cells where toxin expression was induced with anhydrotetracycline was converted to Cy5-labeled cDNA whereas RNA derived from cells in which toxin expression was not induced (treated with ethanol solvent only) was converted to Cy3-labeled cDNA. 6 hours, 24 hours and 72 hours time points were taken for each overexpression condition. Treatments were performed independently a minimum of two times to give independent biological replicates. Hide text

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Characterization of a Clp protease gene regulator and the reaeration response in Mycobacterium tuberculosis.

Sherrid AM, et al. (2010) PLoS One 5(7):e11622

The mechanism by which mycobacteria return to a replicating state upon re-exposure to favorable conditions is not well understood. In this study, we utilized reaeration from a defined hypoxia model to characterize the adaptive response of Mycobacterium tuberculosis (MTB) following a return to favorable growth conditions. Global transcriptional analysis identified the ~100 gene Reaeration Response, induced relative ... Expand to both log-phase and hypoxic MTB. This response includes chaperones and proteases, as well as the transcription factor Rv2745c, a Clp protease gene regulator (ClgR) orthologue. During reaeration, genes repressed during hypoxia are also upregulated in a wave of transcription that includes genes crucial to transcription, translation and oxidative phosphorylation.

Each reaerating culture compared at multiple timepoints to a sample from the same culture at seven days of hypoxia. Three or more replicates at each timepoint. Hide text

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The Differential Gene Expression Pattern of Mycobacterium tuberculosis in Response to Capreomycin and PA-824 versus First-Line TB Drugs Reveals Stress- and PE/PPE-Related Drug Targets.

Fu LM and Tai SC (2009) Int J Microbiol 2009():879621

Tuberculosis is a leading infectious disease causing millions of deaths each year. How to eradicate mycobacterial persistence has become a central research focus for developing next-generation TB drugs. Yet, the knowledge in this area is fundamentally limited and only a few drugs, notably capreomycin and PA-824, have been shown to be active against non-replicating persistent TB bacilli. In this study, we performed a ... Expand new bioinformatics analysis on microarray-based gene expression data obtained from the public domain to explore genes that were differentially induced by drugs between the group of capreomycin and PA-824 and the group of mainly the first-line TB drugs. Our study has identified 42 genes specifically induced by capreomycin and PA-824. Many of these genes are related to stress responses. In terms of the distribution of identified genes in a specific category relative to the whole genome, only the categories of PE/PPE and conserved hypotheticals have statistical significance. Six among the 42 genes identified in this study are on the list of the top 100 persistence targets selected by the TB Structural Genomics Consortium. Further biological elucidation of their roles in mycobacterial persistence is warranted. PMID: 20016672 Hide text

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Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program.

Voskuil MI, et al. (2003) J Exp Med 198(5):705-13

An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible ... Expand significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis. Hide text

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Gene expression diversity among Mycobacterium tuberculosis clinical isolates.

Gao Q, et al. (2005) Microbiology 151(Pt 1):5-14

Intraspecies genetic diversity has been demonstrated to be important in the pathogenesis and epidemiology of several pathogens, such as HIV, influenza, Helicobacter and Salmonella. It is also important to consider strain-to-strain variation when identifying drug targets and vaccine antigens and developing tools for molecular diagnostics. Here, the authors present a description of the variability in gene expression ... Expand patterns among ten clinical isolates of Mycobacterium tuberculosis, plus the laboratory strains H37Rv and H37Ra, growing in liquid culture. They identified 527 genes (15 % of those tested) that are variably expressed among the isolates studied. The remaining genes were divided into three categories based on their expression levels: unexpressed (38 %), low to undetectable expression (31 %) and consistently expressed (16 %). The expression categories were compared with functional categories and three biologically interesting gene lists: genes that are deleted among clinical isolates, T-cell antigens and essential genes. There were significant associations between expression variability and the classification of genes as T-cell antigens, involved in lipid metabolism, PE/PPE, insertion sequences and phages, and deleted among clinical isolates. This survey of mRNA expression among clinical isolates of M. tuberculosis demonstrates that genes with important functions can vary in their expression levels between strains grown under identical conditions. Hide text

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ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response.

Rodriguez GM, et al. (2002) Infect Immun 70(7):3371-81

The mycobacterial IdeR protein is a metal-dependent regulator of the DtxR (diphtheria toxin repressor) family. In the presence of iron, it binds to a specific DNA sequence in the promoter regions of the genes that it regulates, thus controlling their transcription. In this study, we provide evidence that ideR is an essential gene in Mycobacterium tuberculosis. ideR cannot normally be disrupted in this mycobacterium ... Expand in the absence of a second functional copy of the gene. However, a rare ideR mutant was obtained in which the lethal effects of ideR inactivation were alleviated by a second-site suppressor mutation and which exhibited restricted iron assimilation capacity. Studies of this strain and a derivative in which IdeR expression was restored allowed us to identify phenotypic effects resulting from ideR inactivation. Using DNA microarrays, the iron-dependent transcriptional profiles of the wild-type, ideR mutant, and ideR complemented mutant strains were analyzed, and the genes regulated by iron and IdeR were identified. These genes encode a variety of proteins, including putative transporters, proteins involved in siderophore synthesis and iron storage, members of the PE/PPE family, a membrane protein involved in virulence, transcriptional regulators, and enzymes involved in lipid metabolism. Hide text

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A member of the cAMP receptor protein family of transcription regulators in Mycobacterium tuberculosis is required for virulence in mice and controls transcription of the rpfA gene coding for a resuscitation promoting factor.

Rickman L, et al. (2005) Mol Microbiol 56(5):1274-86

Deletion of gene Rv3676 in Mycobacterium tuberculosis coding for a transcription factor belonging to the cAMP receptor protein (CRP) family caused growth defects in laboratory medium, in bone marrow-derived macrophages and in a mouse model of tuberculosis. Transcript profiling of M. tuberculosis grown in vitro identified 16 genes with significantly altered expression in the mutant compared with the wild type. ... Expand Analysis of the DNA sequences upstream of the corresponding open reading frames revealed that 12 possessed sequences related to a consensus CRP binding site that could represent the sites of action of Rv3676. These included rpfA, lprQ, whiB1 and ahpC among genes with enhanced expression in the wild type, and Rv3616c-Rv3613c, Rv0188 and lipQ among genes exhibiting enhanced expression in the mutant. The activity of an rpfA::lacZ promoter fusion was lowered in the Rv3676 mutant and by mutation of the predicted Rv3676 binding site. Moreover, the product of Rv3676 (isolated as a TrxA fusion protein) interacted specifically with the rpfA promoter, and binding was inhibited by mutation of the Rv3676 site. Although Rv3676 retains four of the six amino acid residues that bind cAMP in Escherichia coli CRP addition of cAMP did not enhance Rv3676 binding at the rpfA promoter in vitro. In summary, it has been shown that Rv3676 is a direct regulator of rpfA expression, and because rpfA codes for a resuscitation promoting factor this may implicate Rv3676 in reactivation of dormant M. tuberculosis infections. Hide text

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The mechanism of action of PA-824: Novel insights from transcriptional profiling.

Manjunatha U, et al. (2009) Commun Integr Biol 2(3):215-8

The bicyclic nitroimidazole PA-824 is a pro-drug with a very complex mechanism of action active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. Microarray analysis of the mode of action of PA-824 showed a puzzling mixed effect both on genes responsive to both cell wall inhibition (like isoniazid) and respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug ... Expand appears to involve inhibition of cell wall mycolic acid biosynthesis through an as yet unknown molecular mechanism. However, the structure-activity relationships governing aerobic activity do not parallel the relationships determining anaerobic activity. Based on the metabolite profiling of PA-824 and various derivatives by Ddn-mediated activation, we have shown that PA-824 acts directly as an NO donor.1 This respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by PA-824. The effect of PA-824 on the respiratory complex under hypoxic non-replicating conditions was also manifested in a rapid drop in intracellular ATP levels, again similar to that observed by cyanide treatment. Thus, transcriptional profiling provided valuable clues to elucidating the molecular mechanism of mycobacterial killing. Hide text

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Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection.

Shiloh MU, et al. (2008) Cell Host Microbe 3(5):323-30

Transcriptional profiling of M. tuberculosis growing in log phase treated with various concentrations of carbon monoxide versus untreated controls Keywords: Dose response Two condition experiment, CO treated cells at 2000, 200 and 20 ppm versus untreated controls. Biological replicates: 2 replicates per dose, 1 array per ... Expand replicate Hide text

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The transcriptional regulator Rv0485 modulates the expression of a pe and ppe gene pair and is required for Mycobacterium tuberculosis virulence.

Goldstone RM, et al. (2009) Infect Immun 77(10):4654-67

The pe and ppe genes are unique to mycobacteria and are widely speculated to play a role in tuberculosis pathogenesis. However, little is known about how expression of these genes is controlled. Elucidating the regulatory control of genes found exclusively in mycobacteria, such as the pe and ppe gene families, may be key to understanding the success of this pathogen. In this study, we used a transposon mutagenesis ... Expand approach to elucidate pe and ppe regulation. This resulted in the identification of Rv0485, a previously uncharacterized transcriptional regulator. Microarray and quantitative real-time PCR analysis confirmed that disruption of Rv0485 reduced the expression of the pe13 and ppe18 gene pair (Rv1195 and Rv1196), defined the Rv0485 regulon, and emphasized the lack of global regulation of pe and ppe genes. Hide text

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