RNA-Seq analysis of the TB-019 GSK M72/AS01E trial
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE102574 | GEO | 2023/12/30
REPOSITORIES: GEO
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Project description:In human primary dendritic cells (DC) rapamycin - an autophagy inducer and protein synthesis inhibitor - overcomes the autophagy block induced by Mycobacterium tuberculosis (Mtb) and promotes Th1 response via IL-12 secretion. Here, the immunostimulatory activity of rapamycin in Mtb-infected DC was investigated by analyzing the transcriptome and the translatome profiles. Several differentially expressed genes (DEGs) were found in transcriptome and translatome of Mtb-infected DC, showing an additional increase in presence of rapamycin, which was instead ineffective in uninfected cells. The majority of DEGs identified in the translatome resulted also present in the transcriptome-modulated genes, suggesting that both RNAs are actively translated mRNAs. The DEG in silico analysis showed significant changes in intracellular cascades related to cytokine production, cytokine-induced signaling and immune response to pathogens. In particular, rapamycin treatment of Mtb-infected DC caused a significant enrichment of IFN-beta, IFN-lambda and IFN-stimulated genes in the polysome-associated RNA fraction. In addition, IL-12, IL-23, IL-1B, IL-6, and TNF-A were induced at RNA and protein level by rapamycin in Mtb-infected DC, while IL-10 was reduced. Interestingly, upon siRNA or pharmacologically GSK-3beta inhibition, rapamycin-driven modulation of the pro- and anti-inflammatory cytokine balance was lost, thus indicating that in Mtb-infected DC GSK-3beta functions as molecular switch for the regulation of cytokine milieu. In conclusion, our study sheds light on the molecular mechanism by which autophagy contributes to DC activation during Mtb infection and highlights that rapamycin and its analogs as well as GSK-3beta modulators are promising compounds for host-directed therapy in the control of Mtb infection.
2021-04-12 | GSE163531 | GEO
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Project description:Comparison of gene expression profile of the whiB4 mutant strain of Mycobacterium tuberculosis with the wild type Mycobacterium tuberculosis H37RV Mtb WhiB4 mutant mRNA was compared with the mRNA of wtMtb H37RV under aerobic conditons Aerbic conditions OD600 nm of 0.4, MtbWhiB4KO vs wtMtb, biological replicates: 3 wt Mtb H37RV and 3 MtbWhiB4 KO
2012-07-23 | E-GEOD-37840 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (Mtb) has developed specialized mechanisms to parasitize its host cell, the macrophage. These mechanisms allow it to overcome killing by oxidative burst and persist in the wake of an inflammatory response. Mtb infection in the majority of those exposed is controlled in an asymptomatic form referred to as latent tuberculosis infection (LTBI). HIV is a well-known catalyst of reactivation of LTBI to active TB infection (ATB). Through the use of nonhuman primates (NHPs) co-infected with Mtb and Simian Immunodeficiency Virus (Mtb/SIV), we are able to simulate human progression of TB/AIDS comorbidity. The advantage of NHP models is that they recapitulate the breadth of human TB outcomes, including immune control of infection, and loss of this control due to SIV co-infection. Using macaques infected with Mtb or Mtb/SIV and with different clinical outcomes we attempted to identify signatures between those that progress to active infection after SIV challenge (reactivators) and those that control the infection (non-reactivators).
2022-09-23 | GSE213850 | GEO
Project description:The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific innate immune responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be a deadly disease, only 5-10% of individuals infected with MTB develop active disease, and this inter-individual variation is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacterial pathogens, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. We found that although the gene expression changes were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB. RNA-seq of monocyte-derived macrophages isolated from 6 healthy European males at 4, 18, and 48 hours post-infection with the following 8 bacteria: Mycobacterium tuberculosis (MTB) H37Rv, Mycobacterium tuberculosis GC1237, MTB GC1237, bacillus Calmette-Guérin (BCG), Mycobacterium smegmatis, Yersinia pseudotuberculosis, Salmonella typhimurium, and Staphylococcus epidermidis. table-s1.txt is a tab-delimited text file that contains the batch-corrected log2 counts per million for each of the 156 samples, as well as the Ensembl gene ID and gene name. BCG = bacillus Calmette-Guérin GC = Mycobacterium tuberculosis GC1237 Rv = Mycobacterium tuberculosis (MTB) H37Rv Rv+ = heat-inactivated MTB H37Rv Salm = Salmonella typhimurium Smeg = Mycobacterium smegmatis Staph = Staphylococcus epidermidis Yers = Yersinia pseudotuberculosis
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Project description:Comparison of gene expression profile of the whiB4 mutant strain of Mycobacterium tuberculosis with the wild type Mycobacterium tuberculosis H37RV Mtb WhiB4 mutant mRNA was compared with the mRNA of wtMtb H37RV under aerobic conditons
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Project description:We hypothesized that individuals with immunological sensitization to Mycobacterium tuberculosis (Mtb), conventionally regarded as evidence of latent tuberculosis infection (LTBI), would demonstrate binary responses to preventive therapy. This would reflect the differential immunological consequences of the sterilization of viable infection in those with an active Mtb infection versus no Mtb killing in those who, despite T cell recognition of Mtb antigens, did not harbor viable Mtb bacilli. We investigated the blood transcriptional profiles of 18 individuals with a positive IGRA result and known recent exposure to an index person with isoniazid and rifampicin susceptible pulmonary tuberculosis, at baseline, 2 weeks after initiating combined rifampicin/isoniazid (RH) preventive therapy and at treatment completion. Healthy control volunteers with no history of TB exposure and negative IGRA results were also included. RNA from unstimulated and M. tuberculosis peptide stimulated whole blood (from QuantiFERON TB1 and TB2 tubes) was measured using Agilent microarrays. A set of 474 genes showed the greatest interpersonal and temporal expression variability in antigen-stimulated blood. By performing longitudinal unsupervised clustering analysis with the subset of most variable genes, the IGRA+ participants were separated into two distinct groups. The IGRA-negative controls clustered within one of these groups suggesting that, in contrast to the other subgroup of IGRA+ individuals, RH had no discernible effect in this subgroup. 117 genes were significantly differentially expressed over time between these two groups, with the majority of them associated with immunological pathways known to be important in mycobacterial control. We contend that the different host RNA response reflects lack of Mtb viability in the group that clustered with the IGRA- unexposed healthy controls, and Mtb viability in the one that clustered away. Gene expression patterns in the blood of IGRA+ individuals emerging during the course of RH treatment which reflect Mtb viability could have major implications in the identification of risk of progression/reactivation, treatment stratification and clinical trials for LTBI therapy.
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