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Analysis of the lung transcriptome in Mycobacterium tuberculosis-infected mice reveals major differences in immune response pathways between TB-susceptible and resistant hosts.

ABSTRACT: Using whole genome microarrays, we compared changes in gene expression patterns in the lungs of TB-resistant A/Sn and TB-susceptible I/St mice at day 14 following infection with Mycobacterium tuberculosis H37Rv. Analyses of differentially expressed genes for representation of gene ontology terms and activation of regulatory pathways revealed interstrain differences in antigen presentation, NK, T and B cell activation pathways. In general, resistant A/Sn mice exhibited a more complex pattern and stronger activation of host defense pathways compared to the TB-susceptible I/St mouse strain. In addition, in I/St mice elevated activation of genes involved in neutrophil response was observed and confirmed by quantitative RT-PCR and histopathology. Furthermore, a specific post infection upregulation of cysteine protease inhibitors was found in susceptible I/St mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE64167 | GEO | 2014/12/16

SECONDARY ACCESSION(S): PRJNA270326

REPOSITORIES: GEO

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Analysis of the lung transcriptome in Mycobacterium tuberculosis-infected mice reveals major differences in immune response pathways between TB-susceptible and resistant hosts.

Project description:Using whole genome microarrays, we compared changes in gene expression patterns in the lungs of TB-resistant A/Sn and TB-susceptible I/St mice at day 14 following infection with Mycobacterium tuberculosis H37Rv. Analyses of differentially expressed genes for representation of gene ontology terms and activation of regulatory pathways revealed interstrain differences in antigen presentation, NK, T and B cell activation pathways. In general, resistant A/Sn mice exhibited a more complex pattern and stronger activation of host defense pathways compared to the TB-susceptible I/St mouse strain. In addition, in I/St mice elevated activation of genes involved in neutrophil response was observed and confirmed by quantitative RT-PCR and histopathology. Furthermore, a specific post infection upregulation of cysteine protease inhibitors was found in susceptible I/St mice. To monitor the global transcriptome patterns in the two mouse strains, gene expression was assessed using Agilent 4 x44K whole genome microarrays. Genes that changed their expression level at least two-fold compared to non-infected controls with a p-value of 0.1 were considered as differentially expressed genes (DEG).

2014-12-16 | E-GEOD-64167 | biostudies-arrayexpress

Lung-resident myeloid-derived suppressor cells display dual functionality in experimental tuberculosis

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-1α) 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-4Rα and heightened TB lethality.

2014-12-21 | GSE57124 | GEO

RNA sequencing of neutrophils isolated from lung, spleen and bone marrow of Mycobacterium tuberculosis infected mice

Project description:Mycobacterium tuberculosis infection of mice elicits a robust neutrophil influx that associates with poor outcome from tuberculosis (TB). However, the mechanism by which neutrophils contribute to TB disease pathogenesis is not understood. To gain insights into the pathological functions of neutrophils, the current study performs bulk mRNA sequencing from the neutrophils isolated from lung, spleen and bone marrow of resistant (C57BL/6) and susceptible (IL-1R1 KO) mice at 28 days post M.tuberculosis HN878 infection.

2024-02-29 | GSE203118 | GEO

Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells

Project description:Tuberculosis is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobacterium tuberculosis (MTB), is estimated to have infected up to a third of the world’s population; however, only approximately 10% of healthy individuals progress to active TB disease. Despite evidence for heritability, it is not currently possible to predict whether a healthy person is susceptible to TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from a past episode of active TB. We measured genome-wide gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms in proximity to the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. By intersecting the gene expression and GWAS data, we identified two promising candidate genes: CCL1 and UNC13A. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated decent performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.

2017-01-31 | GSE94116 | GEO

Novel data integration approaches identify concordant and discordant immune responses between mice and humans [mouse]

Project description:We have conducted experiments to compare transcriptional response to tuberculosis (TB) in whole blood in two different TB murine models (susceptible 129S2 strain and resistant C57BL/6 strain) in time points day 1, day 7, day 14 and day 21 after infection.

2017-09-21 | GSE89389 | GEO

Lung-resident myeloid-derived suppressor cells display dual functionality in experimental tuberculosis

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

Whole Genome Sequence Analysis of Mycobacterium tuberculosis Strains from Patients in Campania Region

Project description:Tuberculosis (TB) is one of the deadliest infectious disorders in the world. To effectively TB manage, an essential step is to gain insight into the lineage of Mycobacterium tuberculosis (MTB) strains and the distribution of drug resistance. Although the Campania region is declared a cluster area for the infection, to contribute to the effort to understand TB evolution and transmission, still poorly known, we have generated a dataset of 159 genomes of MTB strains, from Campania region collected during 2018-2021, obtained from the analysis of whole genome sequence data. The results show that the most frequent MTB lineage is the 4 according for 129 strains (81.11%). Regarding drug resistance, 139 strains (87.4%) were classified as multi susceptible, while the remaining 20 (12.58%) showed drug resistance. Among the drug-resistance strains, 8 were isoniazid-resistant MTB (HR-MTB), 7 were resistant only to one antibiotic (3 were resistant only to ethambutol and 3 isolate to streptomycin while one isolate showed resistance to fluoroquinolones), 4 multidrug-resistant MTB, while only one was classified as pre-extensively drug-resistant MTB (pre-XDR). This dataset expands the existing available knowledge on drug resistance and evolution of MTB, contributing to further TB-related genomics studies to improve the management of TB infection.

2023-11-17 | E-MTAB-13058 | biostudies-arrayexpress

Transcription profiling by array of Rifampicin-induced transcriptome response in rifampicin-resistant Mycobacterium tuberculosis

Project description:Tuberculosis (TB) is still a major life-threatening infectious disease, within which especially the rise of multidrug resistant TB (MDR-TB) is currently worrying. This study focuses on mechanisms of development of rifampicin resistance, since rifampicin seems to play an important role in the development of MDR-TB. To provide further insight in rifampicin resistance, we performed a genome-wide transcriptional profile analysis for Mycobacterium tuberculosis (M. tuberculosis) using microarray technology and qRT-PCR analysis. We exposed a rifampicin-susceptible H37Rv wild type (H37Rv-WT) and a rifampicin-resistant progeny H37Rv strain with a H526Y mutation in the rpoB gene (H37Rv-H526Y) to several concentrations of rifampicin, to define the effect of rifampicin on the transcription profile. Our study showed that there are resistance-dependant differences in response between both M. tuberculosis strains. Gene clusters associated with efflux, transport and virulence were altered in the rifampicin-resistant H37Rv mutant compared to the rifampicin-susceptible H37Rv-WT strain after exposure to rifampicin. We conclude that the small gene cluster Rv0559c-Rv0560c in the H37Rv-H526Y strain was remarkably up-regulated in the microarray analysis and qRT-PCR results and appeared to be dependent on rifampicin concentration and time of exposure. Therefore this study suggests that Rv0559c and Rv0560c play a pivotal role in rifampicin resistance of M. tuberculosis. Further investigation of Rv0559c and Rv0560c is needed to reveal function and mechanism of both genes that were triggered upon rifampicin exposure. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-139]

2013-04-21 | E-BUGS-139 | biostudies-arrayexpress

Quantitative proteomic analysis reveals the effects of human neural stem cells on multiple brain regions

Project description:Parkinson’s disease (PD) is one of the most common neurodegenerative disease caused by diminution of neurons in the substantia nigra (SN) which projects dopaminergic (DA) axons to the striatum and other target areas. Recently, accumulating data demonstrated the prospects of cell replacement therapy by using neural stem cell (NSCs) transplantation. However the mechanisms underlying the potential efficacy are not fully understood. To gain new insights into the mechanisms of 6-OHDA induced lesion and potential efficacy of hNSCs transplantation, Intrastriatal 6-Hydroxydopamine (6-OHDA) injected parkinsonian mice were unilaterally engrafted with undifferentiated human NSCs to striatum (ST). High-throughput quantitative proteomic approach was utilized to characterize the proteome profiles of PD related brain regions in these mice including SN, ST, olfactory bulb (OB) and subventricular zone (SVZ). The abundance of more than 5000 proteins with high confidence in each region was determined in this study which represents the most extensive proteomic study of PD mouse models to date. In addition to the disruption of the DA system, the quantitative analysis demonstrated the profound disturbance of SVZ proteome after 6-OHDA insult, in which the abundance of more than 20% proteins was significantly changed. After hNSCs engraftment, the proteome of SVZ was restored and the astrocytes in ST was greatly activated in companion with the increase in neurotrophic factors. Furthermore, bioinformatics analysis demonstrated that changes in proteome was not caused by the proliferation of hNSCs or their progeny, but rather by the reaction of endogenous cells. Overall, this study reveals that hNSCs benefits parkinsonian animals by eliciting endogenous responses in multiple brain regions, and discovers the unexpected role of SVZ cells in PD progress and treatment, providing new therapeutic targets.

2017-03-29 | PXD004152 | Pride

Macrophage responses to MDR M.tuberculosis infection

Project description:The emergence of multidrug resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, resistant to the frontline anti-tubercular drugs rifampicin and isoniazid, forces treatment with less effective and toxic second-line drugs and stands to derail TB control efforts. However, the immune response to MDR Mtb infection remains poorly understood. Here, we determined the RNA transcriptional profile of in vitro generated macrophages to infection with either drug susceptible Mtb HN878 or MDR Mtb W_7642 infection.

2018-12-26 | GSE115495 | GEO

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