Toxoplasma gondii Prevents Chromatin Remodeling Initiated by TLR-Triggered Macrophage Activation

J Immunol. 2009 Jan 1;182(1):489-497

Toxoplasma gondii Prevents Chromatin Remodeling Initiated by TLR-Triggered Macrophage Activation

Leng J, Butcher BA, Egan CE, Abi Abdallah DS, Denkers EY.

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Macrophages infected with the opportunistic protozoan Toxoplasma gondii are unable to up-regulate many proinflammatory cytokine genes, including TNF (TNF-alpha), upon stimulation with LPS and other TLR ligands. In this study, we examined the influence of T. gondii on transcription factors associated with TNF-alpha transcription, as well as phosphorylation and acetylation of histone H3 at distal and proximal regions of the TNF-alpha promoter. During LPS stimulation, we found that Toxoplasma blocks nuclear accumulation of transcription factor c-Jun, but not that of cAMP response element-binding protein or NF-kappaB. However, chromatin immunoprecipitation studies revealed that binding of all of these transcription factors to the TNF promoter was decreased by T. gondii infection. Furthermore, the parasite blocked LPS-induced Ser(10) phosphorylation and Lys(9)/Lys(14) acetylation of histone H3 molecules associated with distal and proximal regions of the TNF-alpha promoter. Our results show that Toxoplasma inhibits TNF-alpha transcription by interfering with chromatin remodeling events required for transcriptional activation at the TNF promoter, revealing a new mechanism by which a eukaryotic pathogen incapacitates proinflammatory cytokine production during infection.

PMID: 19109180 [PubMed - as supplied by publisher]