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Nat Microbiol. 2019 Jul;4(7):1208-1220. doi: 10.1038/s41564-019-0431-8. Epub 2019 Apr 29.

The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-κB signalling via EZH2.

Author information

1
Team Host-Pathogen Interactions and Immunity to Infection, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, France.
2
Université Grenoble Alpes, CEA, INSERM, Grenoble, France.
3
OPTIMAL Small Animal Imaging Facility, Institute for Advanced Biosciences, Grenoble, France.
4
Team Membrane and Cell Dynamics of Host Parasite Interactions, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, France.
5
Team Host-Pathogen Interactions and Immunity to Infection, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, France. alexandre.bougdour@inserm.fr.
6
Team Host-Pathogen Interactions and Immunity to Infection, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, France. mohamed-ali.hakimi@inserm.fr.

Abstract

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.

PMID:
31036909
PMCID:
PMC6591128
[Available on 2019-10-29]
DOI:
10.1038/s41564-019-0431-8

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