Nonconverters exhibit differential transcriptional signatures compared to converters.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211566 | GEO | 2022/08/21
REPOSITORIES: GEO
Similar Datasets
Project description:The dedicated secretion system ESX-1 of Mycobacterium tuberculosis encoded by the extended RD1 region (extRD1) assures export of the ESAT-6 protein and its partner, the 10 kDa culture filtrate protein CFP-10, and is missing from the vaccine strains M.bovis BCG and M.microti. Here, we systematically investigated the involvement of each individual ESX-1 gene in the secretion of both antigens, specific immunogenicity and virulence. ESX-1-complemented BCG and M.microti strains were more efficiently engulfed by bone marrow derived macrophages than controls and this may account for the enhanced in vivo growth of ESX-1 carrying strains. Inactivation of gene pe35 (Rv3872) impaired expression of CFP-10 and ESAT-6 suggesting a role in regulation. Genes Rv3868, Rv3869, Rv3870, Rv3871 and Rv3877 encoding an ATP-dependent chaperone and translocon were essential for secretion of ESAT-6 and CFP-10 in contrast to ppe68 (Rv3873) and Rv3876, whose inactivation did not impair secretion of ESAT-6. A strict correlation was found between ESAT-6 export and the generation of ESAT-6 specific T-cell responses in mice. Furthermore, ESAT-6 secretion and specific immunogenicity were almost always correlated with enhanced virulence in the SCID mouse model. Only loss of Rv3865 and part of Rv3866 did not affect ESAT-6 secretion or immunogenicity, but led to attenuation. This suggests that Rv3865/66 represent a new virulence factor that is independent from ESAT-6 secretion. This study has allowed us to identify new aspects of the extRD1 region of M.tuberculosis and to explore its role in the pathogenesis of tuberculosis. Data is also available from http://bugs.sgul.ac.uk/E-BUGS-31
2007-01-30 | E-BUGS-31 | biostudies-arrayexpress
Project description:New tuberculosis vaccines are highly desirable and urgently needed since the attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) provides only variable efficacy against the pulmonary form of the disease. The region of difference 1 (RD1), which is deleted in BCG and strongly impacts on Mycobacterium tuberculosis (Mtb) virulence and immunogenicity, represents a crucial locus to be engineered for either the improvement of the current BCG vaccine, or the attenuation of Mtb. Therefore, mutants secreting or not wild-type or mutated variants of the RD1-encoded 6 kDa early secreted antigenic target (ESAT-6) were generated. Comparative analysis of the transcriptome, phenotype, cytokine production profiles and the capacity to promote T cell responses were conducted in human primary dendritic cells (DCs), as they represent critical regulators of vaccine-induced immunity, unveiling a distinct immunogenic potential for BCG or Mtb mutants. In contrast to Mtb, BCG induced a poor DC maturation, and to our surprise, a BCG strain complemented with the RD1 region only partially restored DC maturation and expansion of interferon (IFN)-γ producing T cells. In contrast, infection with a recombinant attenuated Mtb strain, secreting a truncated version of ESAT-6 lacking 11 amino acids at the C-terminus portion, drove full maturation in infected DC and maintained their capacity to promote polarization of T helper (Th) 1 cells, as observed upon infection with the virulent Mtb. We performed a comparative microarray analysis of dendritic cells (DCs), infected with Mtb and BCG strains, expressing/complemented (MtbÎRD1::RD1 and BCG::RD1) or not (MtbÎRD1::B412 and BCG::B412) the/with the RD1 region. DCs were challenged with different BCG and Mtb recombinant strains for 8h.
2016-07-03 | E-GEOD-62423 | biostudies-arrayexpress
Project description:New tuberculosis vaccines are highly desirable and urgently needed since the attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) provides only variable efficacy against the pulmonary form of the disease. The region of difference 1 (RD1), which is deleted in BCG and strongly impacts on Mycobacterium tuberculosis (Mtb) virulence and immunogenicity, represents a crucial locus to be engineered for either the improvement of the current BCG vaccine, or the attenuation of Mtb. Therefore, mutants secreting or not wild-type or mutated variants of the RD1-encoded 6 kDa early secreted antigenic target (ESAT-6) were generated. Comparative analysis of the transcriptome, phenotype, cytokine production profiles and the capacity to promote T cell responses were conducted in human primary dendritic cells (DCs), as they represent critical regulators of vaccine-induced immunity, unveiling a distinct immunogenic potential for BCG or Mtb mutants. In contrast to Mtb, BCG induced a poor DC maturation, and to our surprise, a BCG strain complemented with the RD1 region only partially restored DC maturation and expansion of interferon (IFN)-γ producing T cells. In contrast, infection with a recombinant attenuated Mtb strain, secreting a truncated version of ESAT-6 lacking 11 amino acids at the C-terminus portion, drove full maturation in infected DC and maintained their capacity to promote polarization of T helper (Th) 1 cells, as observed upon infection with the virulent Mtb.
2016-01-01 | GSE62423 | GEO
Project description:Despite the discovery of Mycobacterium tuberculosis (Mtb) more than 130 years ago, Mtb physiology and the mechanisms of virulence are still not fully understood. The objective of this study was to compare and characterize the differentially abundant protein profiles of modern, pre-modern and ancient Mtb lineages. Using a comprehensive analysis of the proteome of Mtb lineages 3, 4, 5 and 7, unique and shared proteomic signatures in these modern, pre-modern and ancient Mtb lineages were delineated. Main proteomic findings were verified by using immunoblotting. In addition, analysis of multiple genome alignment of all lineages was performed using Geneious Prime software. Label-free peptide quantification of whole cells from Mtb lineage 3, 4, 5 and 7 yielded 38,346 unique peptides derived from 3092 proteins, representing 77% coverage of the predicted Mtb proteome. Mtb lineage-specific differential abundances was observed for 539 proteins. Lineage 7 exhibited a markedly reduced abundance of proteins involved in DNA repair, type VII ESX-3 and ESX-1 secretion systems, lipid metabolism and inorganic phosphate uptake, and an increased abundance of proteins involved in alternative pathways of the TCA cycle and the CRISPR/Cas system as compared to the other lineages. Lineages 3 and 4 exhibited a higher abundance of proteins involved in virulence, DNA repair, drug resistance and other metabolic pathways. The high throughput analysis of Mtb proteome by super resolution massspectrometry provided an insight into the differential expression of proteins between Mtb lineages 3, 4, 5 and 7 that may explain the slow growth and reduced virulence of lineage 7, as well as metabolic flexibility and the ability to survive under adverse growth conditions.
2020-09-01 | PXD020383 | Pride
Project description:Increasing experimental evidence supports that Mycobacterium tuberculosis (Mtb) has evolved strategies to survive within the lysosomes from activated macrophages, which may represent a reservoir for persistent mycobacteria. To further our knowledge in Mtb response to the lysosomal environment, we profiled the global transcriptional activity of Mtb in a lysosomal in vitro exposure (LivE) model. At inhibitory conditions of lysosomal SF (iLivE), which did not kill but arrested mycobacterial replication thereby mimicking persistence, Mtb expresses a unique transcriptome, where genes involved in general stress response, metabolic reprogramming, cell wall remodeling, respiration, oxidative stress and dormancy response were found to be significantly modulated. Genes encoding for protein families involved in Mtb virulence including ESAT-6, PE-PPE and Mce proteins were also distinctly regulated. Extensive meta-analysis of the Mtb transcriptomes from iLivE and previously reported ex vivo, in vivo and in vitro stress models revealed most significant overlap between iLivE and primary murine macrophage infection model. Our study also highlighted the α-glucan synthesis pathway and a distinct set of toxin-antitoxin systems as toxicity mechanisms that could be exploited as novel antimicrobial approaches for intra-macrophage persistent bacilli. The specificity in responses generated in the LivE model was supported by the significant number of iLivE genes that did not overlap with any of the previously reported in vitro stress models. Finally, to validate the relevance of the LivE model, rv1258c encoding for the efflux pump protein Tap, was selected from the iLivE Mtb transcriptome for further characterization. An Mtb Δrv1258c mutant was constructed and displayed increased susceptibility to killing by lysosomal SF and by the antimicrobial peptide LL-37 found in lysosomes. Furthermore, Δrv1258c Mtb was attenuated in its ability to survive in primary murine macrophages.
2016-04-27 | GSE68337 | GEO
Project description:We present the results of a microarray analysis in which we compare gene expression in CFP+ basal and CFP- luminal epithelia cell populations derived from whole prostates of CK5/CFP adult mice. Several genes that have previously been identified as potential stem cell markers in stem cells from various organs are over-expressed in CFP+ cells relative to CFP- cells.
2010-04-14 | GSE21330 | GEO
Project description:Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.
| S-EPMC7757734 | biostudies-literature
Project description:Although host genetics influences susceptibility to tuberculosis, few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different clinical manifestations of tuberculosis infection would have distinct gene expression profiles, and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from ex vivo Mtb- stimulated macrophages in 12 subjects with 3 clinical phenotypes: latent, pulmonary and meningeal tuberculosis (n=4 per group). After identifying differentially expressed genes, we confirmed these results in 34 additional subjects by real-time PCR. We also used a case-control study design to examine whether polymorphisms in differentially regulated genes were associated with susceptibility to these different clinical forms of TB. We compared gene expression profiles in Mtb-stimulated and unstimulated macrophages and identified 1608 and 199 genes that were differentially expressed by >2 and >5-fold, respectively. Using cluster analysis, we identified gene expression patterns that distinguished the different clinical forms of tuberculosis. In an independent sample set of 34 individuals and a subset of highly regulated genes, 90% of the microarray results were confirmed by RT-PCR, including expression levels of CCL1, which distinguished the 3 clinical groups. Furthermore, 6 single nucleotide polymorphisms (SNPs) in CCL1 were found to be associated with TB in a case-control genetic association study with 273 TB cases and 188 controls. To our knowledge, this is the first identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility. These results suggest that genome-wide studies can provide an unbiased method to identify critical macrophage response genes that are associated with different clinical outcomes and that variation in innate immune response genes regulate susceptibility to tuberculosis. Experiment Overall Design: Latent TB (LTB) subjects were healthy nursing staff members who had worked at a tuberculosis hospital, for more than 20 years and were positive in ESAT-6 and CFP-10- specific IFN-ï?§ ELISPOT assays. All subjects with pulmonary (PTB) and meningeal (TBM) disease had been treated and were free of symptoms at the time of venipuncture. Gene expression of monocyte derived macrophages (MDMs) from subjects with three clinical forms of TB including LTB, PTB and TBM (n = 4 in each group) was examined by microarray. MDMs were stimulated either with a whole cell lysate of M. tuberculosis H37Rv or PBS for 4 hours. RNA expression was analyzed using a Human Genome U133 Plus 2.0 Array (Affymetrix, USA) which contains probe sets for 47,000 transcripts including 38,500 well-characterized human genes.
2009-02-28 | E-GEOD-11199 | biostudies-arrayexpress
Project description:We employed an experimental design where PBMCs from a single donor was sequenced with or without mixing with PBMCs from other healthy unrelated donors in order to determine whether PBMCs engage in an allogeneic response under standard scRNA-seq sample preparation conditions (e.g., 30 minute co-incubation at 4C)
2020-11-13 | GSE161329 | GEO
Project description:The host restricts Mycobacterium tuberculosis (Mtb) access of transition metal ions to inhibit its growth. Cu is essential for the survival of Mtb, but Cu excess is toxic. During co-evolution, Mtb has developed various mechanisms to maintain copper homeostasis. In this report, we firstly found Mtb Rv0102 encoded membrane protein is critical for Mycobacterium Cu uptake. The intracellular Cu level of M. smegmatis (Ms) Rv0102 homolog MSMEG_4702 knockout strain decreased threefold than the wild type, the deletion mutant was more tolerant to higher Cu level. This indicates that Rv0102 is significant for Cu homeostasis and resistance to Cu toxicity. Knocking out the homologous gene MMAR_0267 in M. marinum (Mm) also enhanced its virulence in zebrafish and improved its survival within macrophages. In THP-1 cells infected with Mm, Mm MMAR_0267 deletion mutants’ intracellular survival increased fourfolds and accompanied by less cell apoptosis. Cu deficiency down-regulates the transcription of the M. marinum virulence factor CFP-10, dampening the STING cytosolic signaling in macrophages, fewer IFN-β and less cell apoptosis. These results suggest that Cu is an important factor in inducing cell apoptosis. In summary, mycobacteria can effectively counteract the host's early key nutritional immune mechanisms by regulating copper metabolism, to increase its virulence.
2023-06-30 | GSE235754 | GEO