title: Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses.
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.
authors: Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Gabrielle
authors: 0000-0001-5965-1842
authors: G
authors: Gay
authors: Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Laurence
authors: 0000-0002-0568-3571
authors: L
authors: Braun
authors: Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Marie-Pierre
authors: MP
authors: Brenier-Pinchart
authors: IAB, OPTIMAL Small Animal Imaging Facility, 38000 Grenoble, France.
authors: Julien
authors: 0000-0001-7001-4190
authors: J
authors: Vollaire
authors: IAB, OPTIMAL Small Animal Imaging Facility, 38000 Grenoble, France.
authors: Véronique
authors: 0000-0001-6733-3801
authors: V
authors: Josserand
authors: Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Rose-Laurence
authors: RL
authors: Bertini
authors: Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Aurélie
authors: A
authors: Varesano
authors: IAB, Team Membrane and Cell Dynamics of Host-Parasite Interactions, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Bastien
authors: 0000-0002-2619-9818
authors: B
authors: Touquet
authors: 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.
authors: Pieter-Jan
authors: PJ
authors: De Bock
authors: 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.
authors: Yohann
authors: 0000-0003-3896-6196
authors: Y
authors: Coute
authors: IAB, Team Membrane and Cell Dynamics of Host-Parasite Interactions, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Isabelle
authors: 0000-0002-5677-7463
authors: I
authors: Tardieux
authors: Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, F-38700 Grenoble, France.
authors: Alexandre
authors: 0000-0002-5895-0020
authors: A
authors: Bougdour
authors: 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.
authors: Mohamed-Ali
authors: MA
authors: Hakimi
mesh_terms: D000818:Animals; D002843:Chromatin / Q000502:physiology*; D005786:Gene Expression Regulation; D050856:Interferon Regulatory Factor-1 / Q000032:analysis; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015800:Protozoan Proteins / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D014122:Toxoplasma / Q000502:physiology*
chemical_list: D002843:Chromatin; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D015800:Protozoan Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma