Epigenetic Control of IFN-γ Host Responses During Infection With Toxoplasma gondii

Abstract

Host defense against the human pathogen Toxoplasma gondii depends on secretion of interferon (IFN)-γ and subsequent activation of monocytic cells to combat intracellular parasites. Previous studies have shown that T. gondii evades IFN-γ-mediated immunity by secreting the effector TgIST into the host cell where it binds to STAT1, strengthens its DNA binding activity and recruits the Mi-2/NuRD complex to STAT1-responsive promoters. Here we investigated the impact of the host chromatin environment on parasite interference with IFN-γ-induced gene expression. Luciferase reporters under control of primary and secondary IFN-γ response promoters were only inhibited by T. gondii when they were stably integrated into the host genome but not when expressed from a plasmid vector. Absence of CpG islands upstream and/or downstream of the transcriptional start site allowed more vigorous up-regulation by IFN-γ as compared to CpG-rich promoters. Remarkably, it also favored parasite interference with IFN-γ-induced gene expression indicating that nucleosome occupancy at IFN-γ-responsive promoters is important. Promoter DNA of IFN-γ-responsive genes remained largely non-methylated in T. gondii -infected cells, and inhibition of DNA methylation did not impact parasite interference with host responses. IFN-γ up-regulated histone marks H4ac, H3K9ac, and H3K4me3 but down-regulated H3S10p at primary and secondary response promoters. Infection with T. gondii abolished histone modification, whereas total nuclear activities of histone acetyl transferases and histone deacetylases were not altered. Taken together, our study reveals a critical impact of the host chromatin landscape at IFN-γ-activated promoters on their inhibition by T. gondii with a comprehensive blockade of histone modifications at parasite-inactivated promoters.

Intrinsically disordered pathogen effector alters the STAT1 dimer to prevent recruitment of co-transcriptional activators CBP/p300

“…Although the recruitment of Mi-2/NuRD was not required for the block mediated by the N terminal repeats, it may function in the regulation of other IFN-g induced genes. Consistent with this model, it has recently been suggested that recruitment of Mi-2/NuRD to IFN-g responsive genes is more import in secondary response genes where chromatin modulation may play a more important role 30 .…”

Epigenetic Manipulation of Psychiatric Behavioral Disorders Induced by Toxoplasma gondii

“…Since the posttranslational modification (PTM) of histones plays a key role in epigenetic regulation and chromatin remodeling, similar PTM and gene expression changes in cyst-infected brain tissues would be another research direction to solve the mechanism of behavioral disorders induced by T. gondii. Nast et al (2020) also demonstrated that regulation of host histone marks during interferon gamma (IFN-g) immune response could be broadly inhibited by T. gondii. Until now, only a few of secreting effectors have been described as able to initiate host epigenetic signal: the rhoptry protein ROP16 and ROP18 and the dense granule protein GRA15, GRA16,GRA24, TEEGR, and TgIST.…”

“… Nast et al. (2020) also demonstrated that regulation of host histone marks during interferon gamma (IFN-γ) immune response could be broadly inhibited by T. gondii .…”

The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

“…Multiple epigenetic enzymes have been identified to regulate the production and subsequent effect of IFNs in allogeneic T cells (102)(103)(104). A number of chemical compounds that selectively inhibit these enzymes are made available, and their effect on IFN signaling and therapeutic potentials are under active investigation (104)(105)(106). Since there are very limited reports studying the epigenetic regulation of type I IFNs in the GVHD context, our continual discussion will focus on the epigenetic effects on IFN-g.…”