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

弓形体病期间寄生虫触发的 IFN-g 介导的宿主免疫的表观遗传印记

基本信息

批准号：
252953325
负责人：
Professor Dr. Carsten Lüder
金额：
--
依托单位：
Institut für Medizinische Mikrobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/252953325?language=en
关键词：
Parasite triggered epigenetic imprinting IFN

项目摘要

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.

表观遗传机制调节基因对外界刺激的反应。最近的研究强调，感染性病原体可以通过干扰其宿主的染色质重塑机制来调节宿主的反应。我们已经发现，细胞内寄生虫弓形虫，一种普遍存在的人类和动物的病原体，抑制小鼠巨噬细胞的转录反应，IFN-γ的转录组范围内的规模。这种无反应性伴随着T.包括组蛋白乙酰化减少和IFN-γ应答启动子处染色质重塑复合物组分的募集。值得注意的是，寄生虫感染的巨噬细胞对IFN-γ的不同反应可以通过组蛋白脱乙酰酶抑制剂的治疗来恢复。在这个项目中，寄生虫施加的宿主转录反应的表观遗传抑制，这是与宿主防御T。刚地虫已被阐明。具体而言，将彻底表征来自感染和未感染小鼠巨噬细胞的IFN-g应答启动子处的染色质重塑。此外，染色质生物学的不同调节因子以及寄生虫施加的表观遗传印记中的上游信号级联的影响将被确定。最后，用组蛋白去乙酰化酶抑制剂治疗将揭示它们是否可以在体外在转录组范围内恢复寄生虫感染的巨噬细胞的IFN-g反应，并使小鼠能够控制T。更有效地感染弓形虫。该项目的结果有望阐明病原体施加的表观遗传机制对宿主对细胞内寄生虫的反应的影响，以及这是否可能转化为弓形虫病治疗的新策略。