Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA400176 | ENA |
REPOSITORIES: ENA
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Project description:Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process. Here we report that, in Mtb-infected macrophages, IL-36 signaling modulates cholesterol biosynthesis and efflux via LXR. Moreover, IL-36 induces the expression of cholesterol-converting enzymes and the accumulation of LXR ligands, such as oxysterols. Ultimately, both IL-36 and LXR signaling play a role in the regulation of antimicrobial peptides expression and in Mtb growth restriction. These data provide novel evidence for the importance of IL‑36 and cholesterol metabolism mediated by LXR in cellular host defense against Mtb.
2018-02-14 | GSE103092 | GEO
Project description:A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the antimicrobial mechanism is unclear. Here, we demonstrate that vitamin A mediates host defense through regulation of cellular cholesterol content. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3, the biologically active forms of vitamin A and vitamin D respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Gene expression profiling reveals that ATRA but not 1,25D3 triggers a lipid metabolism and efflux pathway, including expression of lysosomal lipid transport gene NPC2. ATRA-induced decrease in total cellular cholesterol content, subcellular lipid reorganization, lysosomal acidification and antimicrobial activity are all dependent upon expression of NPC2. Finally, the addition of HIV-protease inhibitors known to inhibit cholesterol efflux, Ritonavir and Nelfinavir, blocked both ATRA-induced cholesterol decrease as well as antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated host defense mechanism against M. tuberculosis requires regulation of cellular cholesterol. Monocytes derived from four independent healthy blood donors that were stimulated with control (CTRL), ATRA or 1,25D3 at 10-8M for 18 hours.
2013-12-31 | E-GEOD-46268 | biostudies-arrayexpress
Project description:The upsurge of multidrug-resistant infections has rendered tuberculosis the principal cause of death among infectious diseases. A clonal outbreak multidrug-resistant triggering strain of Mycobacterium tuberculosis was identified in Kanchanaburi Province, designated “MKR superspreader”, which was found to subsequently spread to other regions, as revealed by prior epidemiological reports in Thailand. Herein, we showed that the MKR displayed a higher growth rate upon infection into host macrophages in comparison with the H37Rv reference strain. To further elucidate the MKR’s biology, we utilised RNA-Seq and differential gene expression analyses to identify host factors involved in the intracellular viability of the MKR. A set of host genes function in the cellular response to lipid pathway was found to be uniquely up-regulated in host macrophages infected with the MKR, but not those infected with H37Rv. Within this set of genes, the IL-36 cytokines which regulate host cell cholesterol metabolism and resistance against mycobacteria attracted our interest, as our previous study revealed that the MKR elevated genes associated with cholesterol breakdown during its growth inside host macrophages. Indeed, when comparing macrophages infected with the MKR to H37Rv-infected cells, our RNA-Seq data showed that the expression ratio of IL-36RN, the negative regulator of the IL-36 pathway, to that of IL-36G was greater in macrophages infected with the MKR. Furthermore, the intracellular survival of MKR was diminished with decreased IL-36RN expression. Overall, our results indicate that IL-36RN is critical for MKR intracellular survival and could serve as a new target against this emerging multidrug-resistant M. tuberculosis strain.
2022-10-28 | GSE194017 | GEO
Project description:A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the antimicrobial mechanism is unclear. Here, we demonstrate that vitamin A mediates host defense through regulation of cellular cholesterol content. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3, the biologically active forms of vitamin A and vitamin D respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Gene expression profiling reveals that ATRA but not 1,25D3 triggers a lipid metabolism and efflux pathway, including expression of lysosomal lipid transport gene NPC2. ATRA-induced decrease in total cellular cholesterol content, subcellular lipid reorganization, lysosomal acidification and antimicrobial activity are all dependent upon expression of NPC2. Finally, the addition of HIV-protease inhibitors known to inhibit cholesterol efflux, Ritonavir and Nelfinavir, blocked both ATRA-induced cholesterol decrease as well as antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated host defense mechanism against M. tuberculosis requires regulation of cellular cholesterol.
2013-12-31 | GSE46268 | GEO
Project description:RNA-Seq results accompanying submission of a manuscript: "Cholesterol-dependent transcriptome remodeling reveals new insight into the contribution of cholesterol to Mycobacterium tuberculosis pathogenesis" describing the role of cholesterol and vitamin B12 in shaping the transcriptome of the Mycobacterium tuberculosis H37Rv and M. tuberculosis ∆prpR - propionate regulator (PrpR) mutant. Next generation sequencing results are provided in three independent biological replicates for each strain growing in three different media - minimal medium with glycerol or cholesterol as the sole carbon source and standard 7H9/10% OADC medium. The influence of vitamin B12 on M. tuberculosis transcriptome was analysed on 7H9/10% OADC medium supplemented with B12. The study allowed us to re-establish the list of genes potentially involved in cholesterol metabolism. We further proposed a novel regulatory function of vitamin B12 and PrpR, a propionate regulator, in coordinated cholesterol breakdown metabolite dissipation and virulent phenotype induction. Finally, we demonstrated that a key role of cholesterol in Mtb metabolism is not only providing carbon and energy but also inducing a transcriptome remodeling program that helps in developing tolerance to the unfavorable host cell environment.
2021-05-31 | GSE175812 | GEO
Project description:Tuberculosis remains a major cause of death from an infectious disease worldwide, yet only 10% of people infected with Mycobacterium tuberculosis develop disease. Defining both necessary and sufficient immunologic determinants of protection remains a great scientific challenge. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify human potential candidate markers of host defense by studying gene expression profiles of macrophages, cells which, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene co-expression network analysis revealed an association between the cytokine, IL-32, and the vitamin D antimicrobial pathway in a network of IFN-γ and IL-15 induced ‘defense response’ genes. IL-32 was sufficient for induction of the vitamin D-dependent antimicrobial peptides, cathelicidin and DEFB4, and generation of antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. The IL-15 induced ‘defense response’ macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent vs. active tuberculosis or healthy controls, and a co-expression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15 induced gene network. Inferring that maintaining M. tuberculosis in a latent state and preventing transition to active disease represents host resistance, we believe these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.
2014-08-20 | GSE59184 | GEO
Project description:Tuberculosis remains a major cause of death from an infectious disease worldwide, yet only 10% of people infected with Mycobacterium tuberculosis develop disease. Defining both necessary and sufficient immunologic determinants of protection remains a great scientific challenge. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify human potential candidate markers of host defense by studying gene expression profiles of macrophages, cells which, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene co-expression network analysis revealed an association between the cytokine, IL-32, and the vitamin D antimicrobial pathway in a network of IFN-γ and IL-15 induced ‘defense response’ genes. IL-32 was sufficient for induction of the vitamin D-dependent antimicrobial peptides, cathelicidin and DEFB4, and generation of antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. The IL-15 induced ‘defense response’ macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent vs. active tuberculosis or healthy controls, and a co-expression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15 induced gene network. Inferring that maintaining M. tuberculosis in a latent state and preventing transition to active disease represents host resistance, we believe these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis. Adherent peripheral blood monuclear cells were derived by Ficoll-Hypaque from the whole blood of four healthy donors. Cells adhered to tissue culture-treated plates for 2 h in 1% Fetal Bovine Serum (FBS) in RPMI. Cells were washed then stimulated with IL-10 (10ng/ml), IL-15 (10ng/ml) (R&D Systems), or IL-4 (1U/ml) in RPMI 1640 supplemented with 10% FBS at 37°C, 5% CO2. Cells were harvested at 6 h and 24 h after stimulation and monocytes purified by CD14 microbeads (Miltenyi Biotec) for a confirmed monocyte purity of at least 90%. RNA from purified monocytes extracted by Trizol and purified by Qiagen RNeasy Kit. RNA probe and microarray performed by UCLA Clinical Microarray Core using Ambion labeling kit and Affymetrix Human U133 Plus 2.0 array.
2014-08-20 | E-GEOD-59184 | biostudies-arrayexpress
Project description:IL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. We used microarrays analysis to understand the impact of IL-17A on human monocyte-derived human dendritic cells. We found overexpression of many genes involved in lipid metabolism in IL-17A-treated dendritic cells compared to untreated dendritic cells. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. RNA was extracted from untreated in vitro-generated DC at day 0 (DC, 4 biological replicates ) or DC cultured for 12 days with IL-17A, in the absence or presence of IFN-g (DC-17 and DC-G17, 5 biological replicates)
2015-03-31 | E-GEOD-53163 | biostudies-arrayexpress
Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological. We used transcriptomic analysis to investigate LXR pathway, and cholesterol metabolism in leukemic cells. Malignancy with a poor prognosis that derives from plasmacytoid dendritic cells (PDC). No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared to those of acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL), as well as the transcriptomic signature of primary PDC. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of ATP Binding Cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with three signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor IL-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with an increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.
2017-02-10 | GSE89565 | GEO
Project description:The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics but the benefits are modest, calling for a complete understanding of cholesterol metabolism of intratumoral cells. Low cholesterol levels inhibit T-cell proliferation and cause autophagy mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations of the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXR depletion in CAR-T cells led to improved antitumor function against solid tumor.
2023-04-13 | GSE229611 | GEO