Mycobacterium tuberculosis senses host Interferon gamma via the membrane protein MmpL10
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB56499 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Immune interferon beta and gamma are essential for mammalian host defence against intracellular pathogens. We used microarrays to detail the global programme of gene expression upon interferon-gamma or interferon-beta treatment and identified distinct classes of up-regulated genes.
2017-09-02 | GSE103363 | GEO
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 2] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL‐12, IL‐1 and TNF‐α, as well as IFN‐γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL‐10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. Macrophages were derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNARKO bone marrow, plated and infected with Mtb H37Rv (or not) in triplicate wells. The indicated samples were also treated with 5ng/ml IFNgamma at the time of infection. Samples were then harvested for RNA at time 0, 1hr and 6hr. Please note that *Sample and *Medium control samples (e.g. '0hr TPL2-/-IFNabR-/- Sample' vs '0hr TPL2-/-IFNabR-/- Medium Control Sample') are the same sample group (i.e. uninfected) with one group being a repeat re-run of the other (indicated in the correponding SAMPLE description field).
2013-09-05 | E-GEOD-47673 | biostudies-arrayexpress
Project description:Toxoplasma strains are known to inhibit the expression of several interferon-gamma induced genes, and a type II strain was shown to dysregulate genome-wide responses to interferon-gamma in human fibroblasts (Kim et al., 2007, J Immunol.). In this study we aimed to determine the effect of infection with three clonal lineages of Toxoplasma, type I, II, and III strains on genome-wide interferon-gamma induced transcription in murine macrophages. We also assessed the effect of the two main Toxoplasma modulators of mouse macrophage transcription, ROP16 and GRA15 (Jensen et al., 2011, Cell Host Microbe). We used Affymetrix microarrays to analyze host cell transcription after Toxoplasma infection and interferon-gamma stimulation. RAW264.7 murine macrophages were left uninfected or infected with type I (RH), type I ?rop16 (RH ?rop16), type II (Pru), type II ?gra15 (Pru ?gra15), or type II (CEP) parasites at an MOI ~5 for 18 hours and subsequently stimulated with murine IFN-? for six hours. Plaque assays were done to assess parasite viability. Total RNA was isolated and hybridized to Affymetrix Mouse 430A 2.0 gene chips.
2013-02-19 | E-GEOD-34913 | biostudies-arrayexpress
Project description:Glucocorticoids are extensively used to treat inflammatory diseases, however their chronic intake increases the risk of mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. Here, we studied the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial response, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-gamma, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis (WGCNA), we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-gamma stimulation. This module was linked to the biological functions âautophagyâ, âphagosome maturationâ and âlytic vacuole/lysosomeâ, and contained the vacuolar H+-ATPase (v-ATPase) subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast to IFN-gamma, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the v-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy. Peripheral blood mononuclear cells (PBMCs) of three healthy human donors were isolated by Ficoll-Paque (GE Healthcare). Monocytes were isolated via CD14+ MACS cell separation (Miltenyi Biotec) according to the manufacturers instructions. Monocyte-derived macrophages (MDMs) were prepared by culturing peripheral blood monocytes in RPMI media containing 10% FCS for four to seven days in the presence of M-CSF (50 ng/ml). Afterwards cells were cultured in fresh media with 10% vitamin D-sufficient human AB serum. Cells were stimulated with media, dexamethasone, interferon-gamma and dexamethasone/interferon-gamma for 20h. Total RNA of was isolated with TRIZOL (Life Technologies) and RNA quality was confirmed using micro capillary electrophoresis (2100 Bioanalyzer, Agilent). 100ng RNA was labeled and hybridized to Sureprint G3 human GE 8x60K whole genome mRNA microarray according to the manufacturerâs specifications. The arrays were scanned (Agilent G2595C scanner), data extracted and processed using the Genespring XII software (Agilent).
2016-05-30 | E-GEOD-79077 | biostudies-arrayexpress
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 1] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL?12, IL?1 and TNF??, as well as IFN?? and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL?10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. Macrophages were derived from C57Bl/6 bone marrow, plated and infected with Mtb H37Rv (or not) in duplicate wells. Samples were then harvested for RNA at time 0 (uninfected only), 15m, 30m, 1hr, 3hr, 6hr and 24hr.
2013-09-05 | E-GEOD-47672 | biostudies-arrayexpress
Project description:Toxoplasma strains are known to inhibit the expression of several interferon-gamma induced genes, and a type II strain was shown to dysregulate genome-wide responses to interferon-gamma in human fibroblasts (Kim et al., 2007, J Immunol.). In this study we aimed to determine the effect of infection with three clonal lineages of Toxoplasma, type I, II, and III strains on genome-wide interferon-gamma induced transcription in murine macrophages. We also assessed the effect of the two main Toxoplasma modulators of mouse macrophage transcription, ROP16 and GRA15 (Jensen et al., 2011, Cell Host Microbe). We used Affymetrix microarrays to analyze host cell transcription after Toxoplasma infection and interferon-gamma stimulation.
2013-02-19 | GSE34913 | GEO
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 2] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL‐12, IL‐1 and TNF‐α, as well as IFN‐γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL‐10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease.
2013-09-05 | GSE47673 | GEO
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 1] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL‐12, IL‐1 and TNF‐α, as well as IFN‐γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL‐10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease.
2013-09-05 | GSE47672 | GEO
Project description:Pre-infection with Toxoplasma parasites inhibits induction of an interferon gamma responsive gene expression program. In this study we aimed to determine what role host negative regulatory proteins that are induced by Toxoplasma infection, such as SOCS-1, have in this inhibition. We used Affymetrix microarrays to analyze host cell transcription after pre-treatment with the protein synthesis inhibitor cyclohexamide (CHX), Toxoplasma infection, and subsequent interferon-gamma stimulation. Human foreskin fibroblasts (HFFs) were left untreated or treated with CHX for 40min. Cells were infected, or not, with type I (RH) Toxoplasma parasites, for one hour, and subsequently stimulated with human IFN-γ for one hour. Total RNA was isolated and hybridized to Affymetrix Human U133A 2.0 gene chips.
2015-08-01 | E-GEOD-34916 | biostudies-arrayexpress
Project description:Toxoplasma gondii secretes various virulence effector molecules into host cells to disrupt host interferon-γ (IFN-γ)-dependent immunity. Among the effectors, ROP18 directly phosphorylates and inactivates IFN-inducible GTPases, such as immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs), leading to subversion of IFN-inducible GTPase-induced cell-autonomous immunity. The modes of action of ROP18 have been studied extensively; however, little is known about the molecular mechanism of how ROP18 is produced in the parasite itself. Here, we report a role of T. gondii transcription factor IWS1 in ROP18 mRNA expression in the parasite. Compared with wild-type virulent type I T. gondii, IWS1-deficient parasites showed dramatically increased loading of IRGs and GBPs onto the parasitophorous vacuole membrane (PVM). Moreover, IWS1-deficient parasites displayed decreased virulence in wild-type mice but retained normal virulence in mice lacking the IFN-γ receptor. Furthermore, IWS1-deficient parasites showed severely decreased ROP18 mRNA expression. Ectopic expression of ROP18 in IWS1-deficient parasites restored the decreased loading of effectors onto the PVM and in vivo virulence in wild-type mice. Taken together, these data demonstrate that T. gondii IWS1 regulates ROP18 mRNA expression to determine fitness in IFN-γ-activated host cells and mice.
2023-01-30 | GSE204926 | GEO