Dataset Information

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

ABSTRACT: Host defense against the human pathogen Toxoplasma gondii depends on secretion of interferon (IFN)-? and subsequent activation of monocytic cells to combat intracellular parasites. Previous studies have shown that T. gondii evades IFN-?-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-?-induced gene expression. Luciferase reporters under control of primary and secondary IFN-? 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-? as compared to CpG-rich promoters. Remarkably, it also favored parasite interference with IFN-?-induced gene expression indicating that nucleosome occupancy at IFN-?-responsive promoters is important. Promoter DNA of IFN-?-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-? 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-?-activated promoters on their inhibition by T. gondii with a comprehensive blockade of histone modifications at parasite-inactivated promoters.

SUBMITTER: Nast R

PROVIDER: S-EPMC7544956 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Nast Roswitha R Choepak Tenzin T Lüder Carsten G K CGK

Frontiers in immunology 20200925

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 chromati ...[more]

PMID: 33072127

Similar Datasets

Project description:Toxoplasma gondii (T. gondii) is a parasite infecting animals and humans. In intermediate hosts, such as humans or rodents, rapidly replicating tachyzoites drive vigorous innate and adaptive immune responses resulting in bradyzoites that survive within tissue cysts. Activation of the innate immune system is critical during the early phase of infection to limit pathogen growth and to instruct parasite-specific adaptive immunity. In rodents, dendritic cells (DCs) sense T. gondii through TLR11/12, leading to IL-12 production, which activates NK cells to produce IFN-γ as an essential mechanism for early parasite control. Further, C3 can bind to T. gondii resulting in limited complement activation. Here, we determined the role of C5a/C5aR1 axis activation for the early innate immune response in a mouse model of peritoneal T. gondii infection. We found that C5ar1 -/- animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection in C5ar1 -/- mice was associated with diminished serum concentrations of IL-12, IL-27, and IFN-γ. Importantly, the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6, and TNF-α, as well as several CXC and CC chemokines, were decreased in comparison to wt animals, whereas anti-inflammatory IL-10 was elevated. The defect in IFN-γ production was associated with diminished Ifng mRNA expression in the spleen and the brain, reduced frequency of IFN-γ+ NK cells in the spleen, and decreased Nos2 expression in the brain of C5ar1 -/- mice. Mechanistically, DCs from the spleen of C5ar1 -/- mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulation in vivo and in vitro. Our findings suggest a model in which the C5a/C5aR1 axis promotes IL-12 induction in splenic DCs that is critical for IFN-γ production from NK cells and subsequent iNOS expression in the brain as a critical mechanism to control acute T. gondii infection.

Dataset Information

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

Publications

Epigenetic Control of IFN-γ Host Responses During Infection With <i>Toxoplasma gondii</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets