期刊
PLOS PATHOGENS
卷 8, 期 1, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1002483
关键词
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资金
- Deutsche Forschungsgemeinschaft [LU777/2-2]
Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (M Phi) stimulated with interferon (IFN)-gamma, which is the cytokine crucial for controlling the parasites' replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-gamma. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-gamma in non-infected M Phi, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-gamma. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-gamma-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected M Phi. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-gamma-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-gamma did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected M Phi. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected M Phi are unable to recruit non-muscle actin to IFN-gamma-responsive DNA sequences, which appeared to be independent of stimulation with IFN-gamma and of STAT1 binding. IFN-gamma-induced recruitment of BRG-1 and acetylation of core histones at the IFN-gamma-regulated CIITA promoter IV, but not beta-actin was diminished by >90% in Toxoplasma-infected M Phi as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-gamma regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected M Phi are unable to respond to IFN-gamma due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors.
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