Unknown,Transcriptomics,Genomics,Proteomics

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Toxoplasma TgIST co-opts Host Chromatin Repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses


ABSTRACT: An early hallmark of Toxoplasma 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 Toxoplasma-targeting activities in immune and non-immune cells, but can also contribute to host immune pathology. Toxoplasma 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 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 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 Toxoplasma 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. HFF, 2fTGH (STAT1+/+) and U3A (STAT1-/-) human cells were left uninfected or infected for 24 hours with 76KGFP and 76KGFPÎ?TgIST Toxoplasma strains and stimulated with 100 U/ml IFN-γ for 6 hours before gene expression was measured. Three independent experiments were performed for each condition.

ORGANISM(S): Homo sapiens

SUBMITTER: Mohamed-ali HAKIMI 

PROVIDER: E-GEOD-81613 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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