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Toxoplasma gondii Prevents Chromatin Remodeling Initiated by TLR-Triggered Macrophage Activation¹

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-), upon stimulation with LPS and other TLR ligands. In this study, we examined the influence of T. gondii on transcription factors associated with TNF- transcription, as well as phosphorylation and acetylation of histone H3 at distal and proximal regions of the TNF- 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-B. 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 Ser¹⁰ phosphorylation and Lys⁹/Lys¹⁴ acetylation of histone H3 molecules associated with distal and proximal regions of the TNF- promoter. Our results show that Toxoplasma inhibits TNF- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI50617 (to E.Y.D.) and a Genomics Scholars Award from the Cornell University Center for Vertebrate Genomics (to J.L.).

² Address correspondence and reprint requests to Dr. Eric Denkers, Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401. E-mail address: eyd1{at}cornell.edu

³ Abbreviations used in this paper: pol II, polymerase II; CREB, cAMP-responsive element-binding protein; ChIP, chromatin immunoprecipitation.