Mycobacterium tuberculosis Exploits a Molecular Off Switch of the Immune System for Intracellular Survival
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PROVIDER: PRJNA424972 | ENA |
REPOSITORIES: ENA
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Project description:Mycobacterium tuberculosis (M. tuberculosis) survives and multiplies inside human macrophages by subversion of immune mechanisms. Although these immune evasion strategies are well characterised functionally, the underlying molecular mechanisms are poorly understood. Here we show that during infection of human whole blood with M. tuberculosis, host gene transcriptional suppression, rather than activation, is the predominant response. Spatial, temporal and functional characterisation of repressed genes revealed their involvement in pathogen sensing and phagocytosis, degradation within the phagolysosome and antigen processing and presentation. To identify mechanisms underlying suppression of multiple immune genes we undertook epigenetic analyses. We identified significantly differentially expressed microRNAs with known targets in suppressed genes. In addition, after searching regions upstream of the start of transcription of suppressed genes for common sequence motifs, we discovered novel enriched composite sequence patterns, which corresponded to Alu repeat elements, transposable elements known to have wide ranging influences on gene expression. Our findings suggest that to survive within infected cells, mycobacteria exploit a complex immune “molecular off switch” controlled by both miRNAs and Alu regulatory elements.
2017-12-21 | GSE108363 | GEO
Project description:Mycobacterium tuberculosis (M. tuberculosis) survives and multiplies inside human macrophages by subversion of immune mechanisms. Although these immune evasion strategies are well characterised functionally, the underlying molecular mechanisms are poorly understood. Here we show that during infection of human whole blood with M. tuberculosis, host gene transcriptional suppression, rather than activation, is the predominant response. Spatial, temporal and functional characterisation of repressed genes revealed their involvement in pathogen sensing and phagocytosis, degradation within the phagolysosome and antigen processing and presentation. To identify mechanisms underlying suppression of multiple immune genes we undertook epigenetic analyses. We identified significantly differentially expressed microRNAs with known targets in suppressed genes. In addition, after searching regions upstream of the start of transcription of suppressed genes for common sequence motifs, we discovered novel enriched composite sequence patterns, which corresponded to Alu repeat elements, transposable elements known to have wide ranging influences on gene expression. Our findings suggest that to survive within infected cells, mycobacteria exploit a complex immune "molecular off switch" controlled by both microRNAs and Alu regulatory elements.
| S-EPMC5766484 | biostudies-literature
Project description:Nutritional immunity promotes intracellular survival of nontypeable Haemophilus influenzae via altered intracellular trafficking
2018-05-24 | MSV000082399 | MassIVE
Project description:Previous studies suggest that type I and type II CRISPR-Cas systems were employed to evade host immunity by targeting interference of bacteria’s own genes. Although Mycobacterium bovis (M. bovis) and Mycobacterium tuberculosis (M. tuberculosis) possess integrated type III-A CRISPR-Cas system, its role in mycobacteria remains obscure. Here, we observed that seven cas genes (csm2~6, cas10, cas6) were significantly upregulated under oxidative stress treatment. To explore the function of type III-A CRSIRP-Cas system, Total CRISPR system (TCR) mutant strain was generated in M. bovis Bacille Calmette-Guérin (BCG). Deletion of TCR results in increased sensitivity in response to H2O2 and reduced cell envelope integrity. By using RNA-Seq, 590 differential expression genes were found in mutant for TCR, of which 220 genes were upregulated and 370 genes were downregulated, indicating an important role of TCR in controlling gene expression in mycobacteria. Consistently, disrupting TCR results in poor intracellular survival in vivo and in vitro. Moreover, we showed for the first time that TCR contributed to the regulation of regulatory T cell population, supporting a role of TCR in modulating host immunity. These observations demonstrate that type III-A CRISPR-Cas system as an important factor for intracellular survival and host immunoregulation in mycobacteria, may be a potential target for therapy.
2021-02-05 | GSE166137 | GEO
Project description:Circular RNAs (circRNAs) play a critical role in pathological mechanisms of Mycobacterium tuberculosis (Mtb) and can be used as a new biomarker for active tuberculosis (ATB) diagnosis. Therefore, we identified significantly dysregulated circRNAs in ATB patients and healthy controls (HC) and explored its molecular mechanism. We found that hsa_circ_0002371 was significantly up-regulated in PBMCs of ATB patients and H37Rv- or BCG-infected THP-1 human macrophages. Functional experiments demonstrated that hsa_circ_0002371 inhibited autophagy of BCG-infected THP-1 human macrophages and promoted intracellular BCG survival rate. Mechanistically, hsa_circ_0002371 promoted the expression of hsa-miR-502-5p, and hsa_circ_0002371 overexpression-induced protective effects in BCG-infected THP-1 human macrophages was largely overturned by the inhibition of hsa-miR-502-5p. Notably, hsa-miR-502-5p inhibited autophagy via suppressing autophagy related 16 like 1 (ATG16L1) in BCG-infected macrophages and thus promoting intracellular BCG growth. In summation, hsa_circ_0002371 increased the suppression of hsa-miR-502-5p on ATG16L1 and inhibited autophagy to promote Mtb growth in macrophages. In Conclusion, our data suggested that hsa_circ_0002371 was significantly up-regulated in the PBMCs of ATB patients compared with HC. The hsa_circ_0002371/hsa-miR-502-5p/ATG16L1 axis promoted the survival of intracellular Mtb and inhibited autophagy in macrophages. Our findings suggested hsa_circ_0002371 could act as a potential diagnostic biomarker and therapeutic target.
2024-03-13 | GSE261175 | GEO
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Project description:Host metabolic reprogramming during immune activation promotes intracellular bacterial survival (2DG)
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Project description:We previously showed that increased expression of the principal sigma factor, SigA, mediates the capacity of Mycobacterium tuberculosis 210 strains to grow more rapidly in human monocytes, compared to other strains. To identify SigA-regulated genes that favor intracellular mycobacterial growth, we used microarray analysis to compare gene expression between a recombinant M. tuberculosis 210 strain bearing a sense sigA construct and a vector control during growth in MonoMac6 cells. The most strongly upregulated gene in the sense sigA transformant was Rv2416c, which has previously been shown to enhance intracellular survival of M. smegmatis, and has been designated as eis. Real-time PCR confirmed marked upregulation of eis mRNA by the intracellular sense sigA transformant, and lysates of this transformant contained high concentrations of the Eis protein. Chromatin immunoprecipitation demonstrated that SigA bound the eis promoter region in live bacteria. Deletion of the eis gene reduced growth of M. tuberculosis in macrophages, and complementation of eis reversed this effect. We conclude that SigA regulates eis expression, which in turn contributes to the enhanced capacity of the M. tuberculosis 210 strain to grow in human macrophages.
2009-03-31 | GSE13780 | GEO
Project description:Intracellular pathogens, such as Salmonella enterica serovar Typhimurium (S.Tm), are able to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that are increasingly understood to drive a productive inflammatory response. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here we show that changes in host metabolic state serve as a signal detected byS.Tm. Using metabolic profiling and dual RNA-seq, we show that succinate accumulates in infected macrophages and is sensed by intracellular S.Tm to promote induction of virulence genes. Succinate uptake by the bacterium drives induction of pmrAB-dependent genes and SPI-2 virulence-associated regulon. S.Tm lacking the DcuB transporter for succinate uptake display impaired intracellular survival. Our work demonstrates that accumulation of metabolic intermediates, necessary for macrophage activation, promote intracellular survival of pathogens, opening a new realm of metabolic host-pathogen crosstalk.
2022-10-19 | GSE139207 | GEO
Project description:Intracellular pathogens, such as Salmonella enterica serovar Typhimurium (S.Tm), are able to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that are increasingly understood to drive a productive inflammatory response. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here we show that changes in host metabolic state serve as a signal detected byS.Tm. Using metabolic profiling and dual RNA-seq, we show that succinate accumulates in infected macrophages and is sensed by intracellular S.Tm to promote induction of virulence genes. Succinate uptake by the bacterium drives induction of pmrAB-dependent genes and SPI-2 virulence-associated regulon. S.Tm lacking the DcuB transporter for succinate uptake display impaired intracellular survival. Our work demonstrates that accumulation of metabolic intermediates, necessary for macrophage activation, promote intracellular survival of pathogens, opening a new realm of metabolic host-pathogen crosstalk.
2022-10-19 | GSE139205 | GEO