Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA354792 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5049570.fastq.gz | Fastqsanger.gz | |||
| SRR5049571.fastq.gz | Fastqsanger.gz | |||
| SRR5049572.fastq.gz | Fastqsanger.gz | |||
| SRR5049573.fastq.gz | Fastqsanger.gz | |||
| SRR5049574.fastq.gz | Fastqsanger.gz |
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Project description:Toxoplasma gondii is a ubiquitous apicomplexan parasite of mammals and birds and an important pathogen of humans. IFN-g is the major mediator of host resistance against T. gondii but intriguingly, parasite-infected host cells including macrophages are severely impaired to respond to IFN-g due to defective transcriptional activation of target genes. Here, we tested the possibility that the impaired responsiveness of T. gondii-infected macrophages to IFN-g can be restored by inhibiting histone deacetylases (HDACs) using the class I-specific inhibitor MS-275. Treatment of RAW264.7 cells with MS-275 indeed increased MHC class II surface expression in infected and non-infected cells and largely abolished the inhibition of IFN-g-regulated MHC class II expression exerted by T. gondii. Genome-wide transcriptome profiling revealed that MS-275 increased mean mRNA levels of IFN-g-regulated genes particularly in non-infected macrophages. Transcript levels of 33% of IFN-g secondary response genes but only those of a few primary response genes were also increased by MS-275 in T. gondii-infected cells. Importantly, the unresponsiveness of parasite-infected cells to IFN-g was however not abolished by MS-275. Furthermore, MS-275 also up-regulated several anti-inflammatory cytokines or signaling molecules in T. gondii-infected macrophages. It additionally regulated expression of more than 2500 genes in non-infected macrophages expression of which was surprisingly counteracted by prior infection with T. gondii. FACS analysis and immunofluorescence microscopy revealed that MS-275 did not considerably diminish the number of parasite-positive cells or the intracellular replication in macrophages stimulated or not with IFN-g. Thus, a supportive therapy using MS-275 appears inappropriate for treatment of toxoplasmosis.
2017-02-10 | GSE90478 | GEO
Project description:Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (MΦ) stimulated with interferon (IFN)-γ, which is the cytokine crucial for controlling the parasites’ replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-γ. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-γ in non-infected MΦ, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-γ. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-γ-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected MΦ. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-γ-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-γ did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected MΦ. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected MΦ are unable to recruit non-muscle actin to IFN-γ-responsive DNA sequences, which appeared to be independent of stimulation with IFN-γ and of STAT1 binding. IFN-γ-induced recruitment of BRG-1 and acetylation of core histones at the IFN-γ-regulated CIITA promoter IV, but not β-actin was diminished by >90% in Toxoplasma-infected MΦ as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-γ regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected MΦ are unable to respond to IFN-γ due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors. Comparison of 4 different RNA pools with a 2-Color-Loop Design including 10 microarrays: [1] T. gondii infected and IFN-gamma treated, [2] T. gondii infected and untreated, [3] Non-infected and IFN-gamma treated, and [4] Non-infected and untreated.
2012-01-25 | E-GEOD-28499 | biostudies-arrayexpress
Project description:To study the effect of stress on macrophages due to Toxoplasma, we stimulated murine bone marrow-derived macrophages (BMDMs) with IFN-γ (no-stimulate control) and infected them with the apicomplexan parasite Toxoplasma gondii. scRNA-Seq (10X Chromium genomics ) was performed to understand the changes in the immune cells and study the impact of the parasite.
2024-10-09 | E-MTAB-14453 | biostudies-arrayexpress
Project description:Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (MΦ) stimulated with interferon (IFN)-γ, which is the cytokine crucial for controlling the parasites’ replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-γ. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-γ in non-infected MΦ, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-γ. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-γ-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected MΦ. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-γ-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-γ did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected MΦ. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected MΦ are unable to recruit non-muscle actin to IFN-γ-responsive DNA sequences, which appeared to be independent of stimulation with IFN-γ and of STAT1 binding. IFN-γ-induced recruitment of BRG-1 and acetylation of core histones at the IFN-γ-regulated CIITA promoter IV, but not β-actin was diminished by >90% in Toxoplasma-infected MΦ as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-γ regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected MΦ are unable to respond to IFN-γ due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors.
2012-01-25 | GSE28499 | GEO
Project description:The protozoan parasite Toxoplasma gondii is a highly successful intracellular pathogen, owing in part to its ability to subvert the host immune system. In particular, parasite infection suppresses STAT1 signaling in a variety of cell types, including IFN-γ activated macrophages, via a block within the nucleus. A high-throughput screen to identify genes able to overcome parasite-mediated suppression of STAT1 activity identified 9 transcription factors as enhancers of STAT1 signaling in T. gondii infected cells, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that TLX is a transcriptional regulator that drives the steady-state expression of STAT1-independent genes involved brain function and development, while enhancing the output of a subset of IFN-γ-dependent target genes. Infection of TLX deficient mice with Toxoplasma results in impaired production of interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized function for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense, and reveal that STAT1 activity can be modulated in a context-specific manner by such ‘modifiers’.
2015-05-29 | GSE55750 | GEO
Project description:The protozoan parasite Toxoplasma gondii is a highly successful intracellular pathogen, owing in part to its ability to subvert the host immune system. In particular, parasite infection suppresses STAT1 signaling in a variety of cell types, including IFN-γ activated macrophages, via a block within the nucleus. A high-throughput screen to identify genes able to overcome parasite-mediated suppression of STAT1 activity identified 9 transcription factors as enhancers of STAT1 signaling in T. gondii infected cells, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that TLX is a transcriptional regulator that drives the steady-state expression of STAT1-independent genes involved brain function and development, while enhancing the output of a subset of IFN-γ-dependent target genes. Infection of TLX deficient mice with Toxoplasma results in impaired production of interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized function for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense, and reveal that STAT1 activity can be modulated in a context-specific manner by such ‘modifiers’.
2015-05-29 | GSE55749 | GEO
Project description:Toxoplasma protein phosphatase PPKL TurboID MS data of the paper "The protein phosphatase PPKL is a key regulator of daughter parasite development in Toxoplasma gondii"
| MSV000092840 | MassIVE
Project description:An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii-targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ-stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1+ inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ-mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism.
2016-07-18 | GSE81613 | GEO
Project description:Toxoplasma protein phosphatase PPKL Co-IP MS data of the paper "The protein phosphatase PPKL is a key regulator of daughter parasite development in Toxoplasma gondii".
| MSV000092841 | MassIVE
Project description:To identify accessible chromatin regions in the human host cells during Toxoplasma parasite infection (uninfected, RH-infected and Pru-infected human foreskin fibroblasts) and in the obligate intracellular parasite Toxoplasma gondii (Type 1 RH strain and Type 2 Pru strain), ATAC-seq was performed.
2022-09-30 | GSE209866 | GEO