Closely related parasites trigger distinct innate immune signaling pathways
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: daniel beiting
PROVIDER: E-GEOD-45634 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The closely related protozoan parasites Toxoplasma gondii and Neospora caninum display similar life cycles, subcellular ultrastructure, invasion mechanisms, metabolic pathways, and genome organization, but differ in their host range and disease pathogenesis. Type II (?) interferon has long been known to be the major mediator of innate and adaptive immunity to Toxoplasma infection, but genome-wide expression profiling of infected host cells indicates that Neospora is a potent activator of the type I (?/?) interferon pathways typically associated with antiviral responses. Infection of macrophages from mice with targeted deletions in various innate sensing genes demonstrates that host responses to Neospora are dependent on the toll-like receptor Tlr3 and the adapter protein Trif. Consistent with this observation, RNA from Neospora elicits type I interferon responses when targeted to the host endo-lysosomal system. While live Toxoplasma fails to induce type I interferon, heat-killed parasites do trigger this response, and co-infection studies reveal that T. gondii actively suppresses the production of type I interferon. These findings reveal that eukaryotic pathogens can be potent inducers of type I interferon and that some parasite species, like Toxoplasma gondii, have evolved mechanisms to suppress this response. In vitro cultures of bone marrow-derived macrophages from WT or IFNAR2-/- mice were infected with either Toxoplasma gondii (VEG strain) or Neospora caninum (Nc2 strain) for 17 hours. RNA was collected from biological replicates for expression profiling by microarray. Uninfected controls for both WT and IFNAR2-/- were used as a reference.
2013-03-29 | E-GEOD-45632 | biostudies-arrayexpress
Project description:The closely related protozoan parasites Toxoplasma gondii and Neospora caninum display similar life cycles, subcellular ultrastructure, invasion mechanisms, metabolic pathways, and genome organization, but differ in their host range and disease pathogenesis. Type II (γ) interferon has long been known to be the major mediator of innate and adaptive immunity to Toxoplasma infection, but genome-wide expression profiling of infected host cells indicates that Neospora is a potent activator of the type I (α/β) interferon pathways typically associated with antiviral responses. Infection of macrophages from mice with targeted deletions in various innate sensing genes demonstrates that host responses to Neospora are dependent on the toll-like receptor Tlr3 and the adapter protein Trif. Consistent with this observation, RNA from Neospora elicits type I interferon responses when targeted to the host endo-lysosomal system. While live Toxoplasma fails to induce type I interferon, heat-killed parasites do trigger this response, and co-infection studies reveal that T. gondii actively suppresses the production of type I interferon. These findings reveal that eukaryotic pathogens can be potent inducers of type I interferon and that some parasite species, like Toxoplasma gondii, have evolved mechanisms to suppress this response. Human foreskin fibroblasts (HFF; line BJ-5ta) were cultured to confluency in T25 flasks, infected with one representative of each of the three architypial strains of Toxoplasma gondii: GT1 (type I), Prugniaud (type II) and VEG (type III), or the closely related parasite species, Neospora caninum (strain Nc-Liv). RNA was collected from biological replicates for expression profiling by microarray. Uninfected HFF cells were used as a reference.
2013-03-29 | E-GEOD-45633 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2011-05-27 | E-GEOD-29565 | biostudies-arrayexpress
Project description:This study utilizes global microarray analysis to identify how T. gondii alters its transcriptome in response to the in vivo microenvironment during the innate immune response (four days post-infection) relative to growth in fibroblast cells in vitro. To distinguish changes in the parasite transcriptome dependent or independent of the host immune response the parasite transcriptome was examined in IFN-gamma gene deleted mice in addition to wild type mice.
2012-07-01 | E-MEXP-3579 | biostudies-arrayexpress
Project description:Toxoplasma gondii is a ubiquitous protozoan pathogen able to infect both mammalian and avian hosts. Surprisingly, just three strains appear to account for the majority of isolates from Europe and N. America. To test the hypothesis that strain divergence might be driven by differences between mammalian and avian response to infection, we examine in vitro strain-dependent host responses in a representative avian host, the chicken. To identify parasite drivers of strain-dependent host response, QTL mapping was used; analysis revealed a locus on Toxoplasma chromosome VIIb. To determine whether this was the parasite gene ROP16, array analysis was performed on chicken embryonic fibroblasts infected with Type I parasites and ROP16-KO parasites (of a Type I background). Chicken embryonic fibroblasts were cultivated in vitro and infected with either Type I (RH) parasites or Type I ROP16-KO parasites; ROP16-dependent host transcriptional responses were then analyzed at 5 hours post-infection.
2011-05-27 | E-GEOD-29564 | biostudies-arrayexpress
Project description:miRNA expression profiles of WI38 primary human fibroblasts with an active or inactive p53. Cells were compared under normal untreated conditions (young and proliferating cells), after DNA damage with Doxorubicin, and upon entry into replicative senescence. Keywords: miRNA, WI-38, p53, GSE56, Senescence, Doxorubicin, Cancer, DNA-damage, fibroblasts. 6 samples of WI38 cells were analyzed on 12 Exiqon miRcurry LNA arrays in biological duplicates (2 different cell culture plates for each experimental condition). The six conditions included: 1. [Con_Young] - Primary Young WI38 cells (passage 20) with a control retroviral vector (pLXSN-NEO). Untreated. 2. [GSE_Young] -Primary Young WI38 cells (passage 20) with a retroviral vector encoding for the p53-inactivating peptide GSE56 (pLXSN-NEO-GSE56).Untreated. 3. [Con_Dox] -Primary Young WI38 cells (passage 20) with a control retroviral vector (pLXSN-NEO). Treated with Doxorubicin (0.2 micrograms/ml) for 24 hours). 4. [GSE_Dox] Primary Young WI38 cells (passage 20) with a retroviral vector encoding for the p53-inactivating peptide GSE56 (pLXSN-NEO-GSE56). Treated with Doxorubicin (0.2 micrograms/ml) for 24 hours). 5. [Con_Old] - Sesescent WI38 cells (passage 30) with a control retroviral vector (pLXSN-NEO). Untreated. 6. [GSE_Old] - Senescent WI38 cells (passage 26) with a retroviral vector encoding for the p53-inactivating peptide GSE56 (pLXSN-NEO-GSE56).Untreated. RNA was extracted with TRI-Reagent and sent for labeling and hybridization in Exiqon laboratories (In Denamark). Samples were labeled with Cy5. Reference sample (Cy3) was an RNA mix of all samples. Log2 for Ratio(Cy5/Cy3) was used for further analysis.
2010-05-19 | E-GEOD-12450 | 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. 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:The poly(A)+ and poly(A)− fractions of interacting and non-interacting cells were used for distinct library preparation of interacting and non-interacting prokaryotic pathogen and eukaryotic host cells by deepSuperSAGE. Sequencing was performed with the Illumina HiSeq 2000 platform, and one point of time post infection (early interaction) was additionally prepared by Massive Analysis of cDNA Ends (MACE) as alternative tag-based library preparation method. 10 deepSuperSAGE and 2 MACE libraries. Please consult the publication mentioned in the following for more details.
2015-05-12 | E-GEOD-61730 | biostudies-arrayexpress
Project description:Determine the role of interferons in the transcriptional profile of Ad-F7 transduced primary human macrophages using neutralizing antibody for the type I IFN receptor (IFNAR2). Primary human macrophage preparations were transduced with Ad-GFP or Ad-F7 and treated with control isotype (IgG) or neutralizing antibody for the type I IFN receptor (IFNAR2). RNA was collected 24 hours later and subjected to microarray analysis. Data represents the average of 5 donors.
2008-11-29 | E-GEOD-12002 | biostudies-arrayexpress
Project description:Toxoplasma gondii multiplies inside a parasitophorous vacuole in the host cell. Several parasite proteins have been described that hijack host signaling pathways, which mostly originate from the rhoptry organelles. We report here the identification and characterization of GRA16, the first dense granule protein shown to be exported through the parasitophorous vacuole membrane and to reach the host cell nucleus. Transcriptomic analysis revealed that GRA16 positively modulates the expression of host genes involved in cell-cycle progression and the p53 tumor suppressor pathway. We show that GRA16 directly binds two host enzymes, the deubiquitinase HAUSP and the phosphatase PP2A, and that GRA16 alters p53 protein levels in a HAUSP-dependent manner and induces the nuclear translocation of the PP2A holoenzyme. Therefore GRA16 is a novel regulator of the HAUSP/p53 pathway and together with GRA15, emerge as a subfamily of new dense granule proteins exported beyond the tachyzoites-hosting vacuole to subvert the host transcriptome. Mouse bone marrow-derived macrophages (BMDM) or Human foreskin fibroblasts (HFFs) were infected with the following Toxoplasma gondii strains: - RHku80 WT versus RHku80(deltaGRA16) mutant (in BMDM) - Pruku80 WT versus Pruku80(deltaGRA16) mutant (in BMDM) - RHku80 WT versus RHku80(deltaGRA16) mutant (in HFF)
2013-02-06 | E-GEOD-38779 | biostudies-arrayexpress