Parasite-triggered epigenetic imprinting of IFN-g-mediated host immunity during toxoplasmosis

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Epigenetic mechanisms regulate the expression of genes in response to external stimuli. Recent studies highlight that infectious agents can modulate host responses by interferences with the chromatin remodeling machinery of its host. We have discovered that the intracellular parasite Toxoplasma gondii, a ubiquitous pathogen of humans and animals, inhibits the transcriptional response of mouse macrophages to IFN-g on a transcriptome-wide scale. Such unresponsiveness is accompanied with an impaired chromatin remodeling in T. gondii-infected cells including reduced histone acetylation and recruitment of components of the chromatin remodeling complex at IFN-g-responsive promoters. Remarkably, distinct responses of parasite-infected macrophages to IFN-g can be restored by treatment with inhibitors of histone deacetylases. In this project, the parasite-imposed epigenetic inhibition of the host transcriptional response that is linked to host defense against T. gondii is elucidated. Specifically, the chromatin remodeling at IFN-g-responsive promoters from infected and non-infected mouse macrophages will be thoroughly characterized. Furthermore, the impact of distinct regulators of chromatin biology as well as upstream signaling cascades in the parasite-imposed epigenetic imprinting will be determined. Finally, treatment with histone deacetylase inhibitors will uncover whether they can restore the IFN-g response of parasite-infected macrophages in vitro on a transcriptome-wide scale and enable mice to control T. gondii more efficiently. The results of this project are expected to elucidate the impact of a pathogen-imposed epigenetic mechanism on host responses to an intracellular parasite and whether this might be translated into novel strategies for the therapy of toxoplasmosis.