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

The protozoan parasite Toxoplasma gondii has co-evolved with its homeothermic hosts, human 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 from the host immune killing and colonize the so-called immune privileged tissues where they differentiate into a low replicating stage, is driven by the IL-12 and IFN-γ axis. The recent characterization of a Toxoplasma effector family delivered into the host cell where it rewires the host cell gene expression has allowed identifying 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 NF-κB signaling pathway. Once exported in the host cell TEEGR ends up in the nucleus where it not only complexes with E2F3 and E2F4 host transcription factors to induce gene expression but also promotes shaping of a nonpermissive 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 influencing the host immune response and in mice promotes parasite persistence.