Project description:The purpose of this study was to identify genes that are differentially expressed under conditions of potassium limitation, to elucidate how Mycobacterium tuberculosis (Mtb) senses and responds to ionic changes, and the role of these responses in host colonization.
Project description:Dormant Mycobacterium tuberculosis bacilli play important role in latent tuberculosis infection. Previously we have demonstrated that cultivation of M. tuberculosis in potassium-deficient media resulted in the generation of dormant ‘non-culturable’ cells. Addition of a moderate concentration of rifampicin enabled to kill a minor subpopulation of actively replicating bacilli and obtain a homogeneous ‘zero-CFU’ population of dormant cells characterized by total inability to produce colonies on solid media and by high potential to reactivate after reintroducing of potassium. An RNA-seq based transcriptome analysis of this dormant ‘zero-CFU’ population revealed a 30-50 fold decrease of the total level of mRNA in the cells, indicating global shift-down of gene expression level. The residual scarce protein-coding transcriptome of the dormant cells showed decreased abundance of mRNAs encoding ribosomal proteins and enzymes of TCA cycle and respiratory chain, and increased abundance of mRNAs encoding PE-PGRS proteins. Interestingly, the transcriptome of dormant cells showed little changes during several days of persistence. This stability of ‘dormant’ transcripts may reflect their readiness for translation upon resuscitation process. Transition of M. tuberculosis cells to dormancy was accompanied by the cleavage of 23S ribosomal RNA at a specific point, located outside the ribosome catalytic center. Another feature of the ‘dormant’ transcriptome was an increased abundance of non-coding transcripts. Enrichment of "dormant transcriptome" by small non-coding RNAs playing regulatory function in the cell probably indicates their role in transition to and maintenance of dormant ‘non-culturable’ state.
Project description:Dormancy in non-sporulating bacteria is an interesting and underexplored phenomenon with significant medical implications. In particular, latent tuberculosis may result from the maintenance of Mycobacterium tuberculosis bacilli in non-replicating states in infected individuals. Uniquely, growth of M. tuberculosis in aerobic conditions in potassium-deficient media resulted in the generation of bacilli that were non-culturable (NC) on solid media but detectable in liquid media. These bacilli were morphologically distinct and tolerant to cell-wall-targeting antimicrobials. Bacterial counts on solid media quickly recovered after washing and incubating bacilli in fresh resuscitation media containing potassium. This resuscitation of growth occurred too quickly to be attributed to M. tuberculosis replication. Transcriptomic and proteomic profiling through adaptation to, and resuscitation from, this NC state revealed a switch to anaerobic respiration and a shift to lipid and amino acid metabolism. High concordance with mRNA signatures derived from M. tuberculosis infection models suggests that analogous NC mycobacterial phenotypes may exist during disease and may represent unrecognized populations in vivo. Resuscitation of NC bacilli in potassium-sufficient media was characterized by time-dependent activation of metabolic pathways in a programmed series of processes that probably transit bacilli through challenging microenvironments during infection. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-151]
Project description:This SuperSeries is composed of the following subset Series: GSE6209: The global transcriptional profile of Mycobacterium tuberculosis during human macrophages infection GSE7962: Sigma factor E of Mycobacterium tuberculosis controls the expression of bacterial components that modulate macrophages Keywords: SuperSeries Refer to individual Series
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug clofazamine. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug pretomanid. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug isoniazid. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug Rifampicin. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug Moxifloxacin. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug linezolid. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.