Mycobacterium tuberculosis
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ABSTRACT:
PROVIDER: PRJNA248476 | ENA |
REPOSITORIES: ENA
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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
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 Δlsr2 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 Δlsr2 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 Δlsr2 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.
2014-05-24 | GSE57948 | GEO
Project description:Two billion people are estimated to have latent tuberculosis infection associated with dormant Mycobacterium tuberculosis. Mycobacteria possess a great portfolio of regulatory proteins which that control transitions betweento dormancy and resuscitation, including the essential protein kinase B (PknB). Here, we established that depletion of PknB resulted in global alteration of the M. tuberculosis transcriptome, and identified and implicated the DNA-binding protein Lsr2 as a main transcriptional regulator likely responsible for these changes. Furthermore, we showed that Lsr2 was phosphorylated by PknB in vitro and phosphorylation of Lsr2 on threonine 112 was important for M. tuberculosis growth and survival in the Wayne non-replicating persistence model. Our fluorescence anisotropy and electromobility shift assays revealed demonstrated that phosphorylation prevented reduced affinity of Lsr2 binding to DNA, and ChHIP-sequencing experiments confirmed increased DNA binding by of a phosphoablative (T112A) Lsr2 mutant in M. tuberculosis. According to our structural modelling studies revealed that phosphomimetic T112D mutation (T112D) to Lsr2 resulted in increased dynamics of the C-terminal part and a shift of the DNA binding loop of in the Lsr2 DNA binding domain, which disrupted prevented the DNA-protein interactions. Our findings suggest that PknB- mediated phosphorylation of Lsr2 is necessary for fine- tuning of gene expression during M. tuberculosis growth and transition to dormancy enabling M. tuberculosis to adapt and survive to cause disease.
2019-10-02 | E-MTAB-7627 | biostudies-arrayexpress
Project description:Bacterial nucleoid-associated proteins play important roles in chromosome organization and global gene regulation. We find that Lsr2 of Mycobacterium tuberculosis is a novel nucleoid-associated protein that specifically binds AT-rich regions of the genome, including regions encoding major virulence factors, such as the ESX secretion systems, the lipid virulence factors PDIM/PGL, and the PE/PPE families of antigenic proteins. Comparison of genome-wide binding data with expression data indicates that Lsr2 binding results in transcriptional repression. Domain swamping experiments demonstrate that Lsr2 has an N-terminal dimerization domain and a C-terminal DNA binding domain. NMR analysis of the DNA binding domain of Lsr2 and its interaction with DNA reveals a novel structure and a unique mechanism that enables Lsr2 to discriminately target AT-rich sequences through interactions with the minor groove of DNA. Taken together, we provide evidence that mycobacteria have employed a structurally distinct molecule with an apparently different DNA recognition mechanism to achieve an equivalent function as the Enterobacteriaceae H-NS, coordinating global gene regulation and virulence in this group of medically important bacteria. Comparison of Lsr2 chromatin-immunoprecipitated DNA sequences to total reference DNA
2010-06-19 | E-GEOD-18652 | biostudies-arrayexpress
Project description:Bacterial nucleoid-associated proteins play important roles in chromosome organization and global gene regulation. We find that Lsr2 of Mycobacterium tuberculosis is a novel nucleoid-associated protein that specifically binds AT-rich regions of the genome, including regions encoding major virulence factors, such as the ESX secretion systems, the lipid virulence factors PDIM/PGL, and the PE/PPE families of antigenic proteins. Comparison of genome-wide binding data with expression data indicates that Lsr2 binding results in transcriptional repression. Domain swamping experiments demonstrate that Lsr2 has an N-terminal dimerization domain and a C-terminal DNA binding domain. NMR analysis of the DNA binding domain of Lsr2 and its interaction with DNA reveals a novel structure and a unique mechanism that enables Lsr2 to discriminately target AT-rich sequences through interactions with the minor groove of DNA. Taken together, we provide evidence that mycobacteria have employed a structurally distinct molecule with an apparently different DNA recognition mechanism to achieve an equivalent function as the Enterobacteriaceae H-NS, coordinating global gene regulation and virulence in this group of medically important bacteria.
2009-11-15 | GSE18652 | GEO
Project description:Mycobacterium abscessus (Mabs) is a fast-growing, non-tuberculous mycobacterium responsible for serious lung infections in patients with cystic fibrosis. This bacterium evolves during the pulmonary infection between a smooth (S) and a rough morphotype (R). We have previously isolated the lsr2 gene as being differentially expressed during the transition between Mabs-S and Mabs-R. lsr2 encodes a pleiotropic transcription factor belonging to the superfamily of nucleoid-associated proteins (NAPs), which play an essential role in the hierarchical organization of bacterial chromosomes. The present study aims to unravel the molecular role of Lsr2 in regulating expression of gene involved in the adaptation and the pathobiology of Mabs using both RNA-Seq and ChIP-seq.
2023-11-30 | GSE239869 | GEO
Project description:Mycobacterium abscessus (Mabs) is a fast-growing, non-tuberculous mycobacterium responsible for serious lung infections in patients with cystic fibrosis. This bacterium evolves during the pulmonary infection between a smooth (S) and a rough morphotype (R). We have previously isolated the lsr2 gene as being differentially expressed during the transition between Mabs-S and Mabs-R. lsr2 encodes a pleiotropic transcription factor belonging to the superfamily of nucleoid-associated proteins (NAPs), which play an essential role in the hierarchical organization of bacterial chromosomes. The present study aims to unravel the molecular role of Lsr2 in regulating expression of gene involved in the adaptation and the pathobiology of Mabs using both RNA-Seq and ChIP-seq.
2023-11-30 | GSE239870 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE21111: Basal in vitro transcriptomes of Mycobacterium tuberculosis complex (MTC) clinical isolates GSE21112: Intracellular transcriptional adaptation of Mycobacterium tuberculosis complex (MTC) clinical isolates inside resting murine macrophages GSE21113: Intracellular transcriptional adaptation of Mycobacterium tuberculosis complex (MTC) clinical isolates inside activated murine macrophages Refer to individual Series
2010-07-09 | E-GEOD-21114 | biostudies-arrayexpress
Project description:The adaptation strategies and regulatory networks behind the adaptation of D. shibae DFL12T to changing oxygen regimes was investigated. Moreover, the essential role of 4 Crp/ Fnr like regulators within this adaptation process was revealed using transcriptional analysis of regulator knock out strains.
2017-01-17 | GSE93652 | 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