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J Exp Med. 2016 Aug 22;213(9):1779-98. doi: 10.1084/jem.20160340. Epub 2016 Aug 8.

Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses.

Author information

1
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
2
IAB, OPTIMAL Small Animal Imaging Facility, 38000 Grenoble, France.
3
IAB, Team Membrane and Cell Dynamics of Host-Parasite Interactions, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
4
Institut de Biosciences et Biotechnologies de Grenoble-Laboratoire Biologie à Grande Échelle (BIG-BGE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INSERM, 38000 Grenoble, France.
5
Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France mohamed-ali.hakimi@inserm.fr.

Abstract

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.

PMID:
27503074
PMCID:
PMC4995087
DOI:
10.1084/jem.20160340
[Indexed for MEDLINE]
Free PMC Article

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