The global transcriptome of whole lungs extracted from M. tuberculosis infected C57BL6 mice
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ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2500, Qubit 2.0, Agilent 2100
ORGANISM(S): Mus musculus
SUBMITTER: Bichitra Kumar Biswal
PROVIDER: E-MTAB-8663 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:RNA-seq analysis was performed using RNA isolated from three tumor models (GL261 glioma, LLC Lewis lung carcinoma, B16F10 melanoma) implanted subcutaneousy in C57BL/6 mice, or in ICR scid mice. Mice were untreated or were treated with cyclophosphamide (CPA) given on a 6-day repeating metronomic schedule (CPA/6d), except as noted. Results from these global transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong activation by CPA/6d treatment of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment was found to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) â which results in a strong but transient natural killer cell response followed by early tumor growth rebound â induced fewer cytokines and increased expression of drug metabolism genes. Taken together, these findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules. RNA isolated from various tumor cell lines implanted s.c in C57BL/6 mice or scid mice, untreated or treated with cyclophosphamide (CPA) given on a metronomic schedule, were prepared and used for stranded or unstranded RNA-seq.
2016-08-01 | E-GEOD-71491 | biostudies-arrayexpress
Project description:Background Accurate assessment of treatment efficacy would facilitate clinical trials of new anti-tuberculosis drugs. TB patients exhibit altered peripheral immunity which reverts during successful treatment. We hypothesised that these changes could be observed in whole blood transcriptome profiles. Methods Ex vivo blood samples from 27 pulmonary TB patients were assayed at diagnosis and during conventional treatment. RNA was processed and hybridised to Affymetrix GeneChips, to determine expression of over 47,000 transcripts. Findings There were significant changes in expression of over 4,000 genes during treatment. Rapid, large scale changes were detected, with down-regulated expression of ~1,000 genes within the first week, including inflammatory markers such as the complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B cell markers, transcription factors and signalling molecules. Interpretation The expression of many genes is drastically altered during TB disease, with components of the humoral immune response being markedly affected. The treatment-induced restoration reflects the simultaneous suppression and activation of different immune responses in TB. The rapid initial down-regulation of expression of inflammatory mediators coincides with rapid killing of actively dividing bacilli, whereas slower delayed changes occur as drugs act on dormant bacilli and as lung pathology resolves. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity. Ex vivo blood samples analysed for 27 first episode pulmonary TB patients, at diagnosis and after 1, 2, 4 and 26 weeks of treatment.
2012-08-09 | E-GEOD-31348 | biostudies-arrayexpress
Project description:Background Accurate assessment of treatment efficacy would facilitate clinical trials of new anti-tuberculosis drugs. TB patients exhibit altered peripheral immunity which reverts during successful treatment. We hypothesised that these changes could be observed in whole blood transcriptome profiles. Methods Ex vivo blood samples from 27 pulmonary TB patients were assayed at diagnosis and during conventional treatment. RNA was processed and hybridised to Affymetrix GeneChips, to determine expression of over 47,000 transcripts. Findings There were significant changes in expression of over 4,000 genes during treatment. Rapid, large scale changes were detected, with down-regulated expression of ~1,000 genes within the first week, including inflammatory markers such as the complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B cell markers, transcription factors and signalling molecules. Interpretation The expression of many genes is drastically altered during TB disease, with components of the humoral immune response being markedly affected. The treatment-induced restoration reflects the simultaneous suppression and activation of different immune responses in TB. The rapid initial down-regulation of expression of inflammatory mediators coincides with rapid killing of actively dividing bacilli, whereas slower delayed changes occur as drugs act on dormant bacilli and as lung pathology resolves. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity. Ex vivo blood samples analysed during TB treatment. These samples are from 9 successfully cured patients at diagnosis and end-of-treatment at 26 weeks.
2012-08-09 | E-GEOD-36238 | biostudies-arrayexpress
Project description:DNA-methylation is a vital epigenetic mark that participates in establishing and maintaining chromatin structures and in regulating gene transcription during mammalian development and cellular differentiation. Inter-individual differences in methylation patterns may represent a major source of phenotypic variation, however, the determinants, inheritance, extent, and consequences of such differences are poorly understood. Here we have analysed methylation profiles of immune cells from two inbreed mouse strains (C57BL/6 & BALB/c) that represent prototypic models for Th1- or Th2-dominated immune responses. Using a methyl-CpG immunoprecipitation approach, genomes were fractionated into methylated and unmethylated genome pools and separately analysed at 180 genomic regions (covering 28 Mb of the mouse genome) that were selected based on differential gene expression between both mouse strains. Differentially methylated regions are detected by analyzing array probes for diametrically opposed enrichment behaviour between both hybridizations (e.g. a region that is relatively enriched in the unmethylated pool of BALB/c and shows reverse enrichment behaviour in the methylated pool is considered hypomethylated in BALB/c). The integrated analysis of hypo and hypermethylation profiles allowed the identification of several hundred differentially methylated regions, but also uncovered regions that were duplicated in one strain, contained single nucleotide polymorphisms or micro- and macro-deletions. Keywords: MCIp-on-Chip; comparative genomic hybridization Methylation profiles of regions, harbouring differentially expressed genes in BMM, were compared between C57BL/6 and BALB/c. Two independently grown, harvested and MCIp treated gDNA preparations were used for each mouse strain (Two biological replicates; One replicate per array). Hypo- and hypermethylated pools serve as diametrically oposed technical replicates (mirror approach).
2010-05-15 | E-GEOD-14463 | biostudies-arrayexpress
Project description:The intent of the experiment is to study the reactivity of human primary blood monocytes during a physiological or pathological inflammation. We designed two in vitro models that recapitulate the different phases of the reaction (recruitment, initiation, development, and resolution - \\"resolving model\\" - vs. persistence of inflammation \"persistent model): monocytes were exposed to different stimuli (microbial molecules, cytokines, and Immune complexes), and to sequential changes in microenvironmental conditions (temperature, hypoxia, amount of serum), at different time points (0, 4, 14, 24, 48 h for the resolving model and 0, 2, 4, 14, 24, 72, 96 h for the persistent model).
2020-06-30 | E-MTAB-8226 | biostudies-arrayexpress
Project description:Using cell-based approaches and experimental mouse models for pulmonary TB we unveiled MDSCs as new myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). MDSCs readily phagocytosed Mtb, released proinflammatory (IL-6, IL-1M-NM-1) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in disease-resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4RM-NM-1 and heightened TB lethality. Microarray experiments were performed as dual-color hybridizations on Agilent mouse whole genome catalog 44K arrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied.
2014-12-21 | E-GEOD-57124 | biostudies-arrayexpress
Project description:Background Identification of patients at risk of tuberculosis relapse following treatment would revolutionize clinical trials of new drugs and regimens and facilitate clinical management. The study aim was to determine whether tuberculosis patients who subsequently suffer relapse have different immune responses to mycobacteria in vitro compared to patients who remain cured for two years post-treatment. Methods First episode pulmonary tuberculosis patients were recruited into a surrogate marker study in Cape Town, South Africa. Peripheral blood samples were collected at diagnosis and after two and four weeks of tuberculosis treatment. Diluted blood was cultured with live Mycobacterium tuberculosis for six days and cellular RNA was frozen. Gene expression in samples from ten patients who subsequently relapsed, confirmed by stain genotyping, was compared to those who remained cured using Affymetrix microarrays. Results At diagnosis, the expression of 668 genes was significantly different in samples from patients who subsequently relapsed compared to successfully cured patients, and these differences persisted for at least four weeks. Gene Ontology and biological pathways analyses revealed the most significant difference was up-regulation of genes involved in cytotoxic cell-mediated killing, such as perforin, granulysin and fas ligand. Results were confirmed by qRT-PCR in a wider patient cohort. Conclusions These data show that patients who will subsequently relapse exhibit altered immune responses at diagnosis, including excessively robust cytolytic responses to M. tuberculosis in vitro, compared to patients who will achieve durable cure. Together with microbiological and clinical indices, these differences could be exploited for patient stratification in drugs trials, or for host-directed therapy development. Venous blood samples were diluted in culture medium and stimulated with live M. tuberculosis for 6 days. Samples from 10 TB patients who subsequently relapsed and 10 patients whore remained disease-free for 2 years. Samples collected at TB diagnosis and after 2 weeks or 4 weeks of treatment of first TB episode.
2015-09-10 | E-GEOD-67589 | biostudies-arrayexpress
Project description:Molecular profiling of effect of TNFα neutralization in contrast to anti-IL-17A or anti-IL-17F treatment for 28 days in lungs of M. tuberculosis infected C57BL/6 mice. Animals were treated once per week (starting day-1) with anti-mouse IL-17A or IL-17F antibodies (20 mg/kg i.p.), anti-mouse TNFα antibody (10 mg/kg), respective isotype control antibodies. Moreover, infected and non-infected TNFα-deficient mice were also analysed. Gene expression data revealed major changes of inflammatory and immune gene expression signatures 4 weeks post-infection (including host-pathogen interactions, macrophage recruitment, activation and polarization, host-anti-mycobacterial activities, immunomodulatory responses and extracellular matrix metallopeptidases) after TNFα blockade, while IL-17A or IL-17F neutralization elicited only mild changes of few genes without impaired host resistance four weeks after M. tuberculosis infection.
2016-12-02 | E-MTAB-5218 | biostudies-arrayexpress
Project description:To gain insight into the host cell types, cellular and molecular pathways possibly involved in the differential permissiveness to pulmonary replication of M. tuberculosis, we carried out transcript profiling studies on M. tuberculosis-infected lungs from congenic and parental strains. We were particularly interested in two groups of transcripts. The first group consists of transcripts which expression in the lung is regulated in response to M. tuberculosis infection (global response to infection), and that is obtained by comparing transcripts profiles of infected vs. uninfected lungs. The second group of transcripts is associated with increased resistance to M. tuberculosis infection of B6 and D2.B6-Chr7 mice. That list consists in the overlap between the lists commonly expressed in response to infection between resistant B6 and D2.B6-Chr7 but that show a significant difference in modulation when compared to infected susceptible D2.<br><br> In these experiments, B6, D2 as well as the D2.B6-Chr19, and D2.B6-Chr7 congenic lines were infected with M. tuberculosis and lungs were harvested at day 30 and day 70, and RNA was prepared. Three independent RNA samples from each group were converted to labeled cDNAs and hybridized to Affymetrix oligonucleotides arrays (Mouse Genome 430 2.0 array). Hybridization results were analyzed with the Genesifter analysis program to characterize changes in gene expression.
2009-02-20 | E-MEXP-1942 | biostudies-arrayexpress
Project description:Immune responses in lungs of Coronavirus Disease 2019 (COVID-19) are poorly characterized. We conducted transcriptomic, histologic and cellular profiling of post mortem COVID-19 and normal lung tissues. Two distinct immunopathological reaction patterns were identified. One pattern showed high expression of interferon stimulated genes (ISGs) and cytokines, high viral loads and limited pulmonary damage, the other pattern showed severely damaged lungs, low ISGs, low viral loads and abundant immune infiltrates. Distinct patterns of pulmonary COVID-19 immune responses correlated to hospitalization time and may guide treatment and vaccination approaches.
2020-09-02 | GSE151764 | GEO