The protozoan parasite Toxoplasma gondii has co-evolved with its homeothermic hosts (humans included) strategies that drive its quasi-asymptomatic persistence in hosts, hence optimizing the chance of transmission to new hosts. Persistence, which starts with a small subset of parasites that escape host immune killing and colonize the so-called immune privileged tissues where they differentiate into a low replicating stage, is driven by the interleukin 12 (IL-12)–interferon-γ (IFN-γ) axis. Recent characterization of a family of Toxoplasma effectors that are delivered into the host cell, in which they rewire the host cell gene expression, has allowed the identification of regulators of the IL-12–IFN-γ axis, including repressors. We now report on the dense granule-resident effector, called TEEGR (Toxoplasma E2F4-associated EZH2-inducing gene regulator) that counteracts the nuclear factor-κB (NF-κB) signalling pathway. Once exported into the host cell, TEEGR ends up in the nucleus where it not only complexes with the E2F3 and E2F4 host transcription factors to induce gene expression, but also promotes shaping of a non-permissive chromatin through its capacity to switch on EZH2. Remarkably, EZH2 fosters the epigenetic silencing of a subset of NF-κB-regulated cytokines, thereby strongly contributing to the host immune equilibrium that influences the host immune response and promotes parasite persistence in mice.
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This work was supported by the Laboratoire d’Excellence (LabEx) ParaFrap (ANR-11-LABX-0024), the Agence Nationale pour la Recherche (Project HostQuest, ANR-18-CE15-0023) and the European Research Council (ERC Consolidator grant no. 614880 Hosting TOXO to M.-A.H.). The proteomic experiments were partly supported by the Agence Nationale pour la Recherche (Investissement d’Avenir Infrastructures, ProFi project ANR-10-INBS-08-01).
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–10 and Supplementary Table legends.
Differentially expressed genes between human cells infected with Pruku80 and Pruku80teegr.
Differentially expressed genes between murine BMDMs infected with Pruku80 and Pruku80teegr.
Strains, vectors and primers.
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