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      Toxoplasma gondii dysregulates IFN-gamma-inducible gene expression in human fibroblasts: insights from a genome-wide transcriptional profiling.

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          Abstract

          Toxoplasma gondii is an obligate intracellular parasite that persists for the life of a mammalian host. The parasite's ability to block the potent IFN-gamma response may be one of the key mechanisms that allow Toxoplasma to persist. Using a genome-wide microarray analysis, we show here a complete dysregulation of IFN-gamma-inducible gene expression in human fibroblasts infected with Toxoplasma. Notably, 46 of the 127 IFN-gamma-responsive genes were induced and 19 were suppressed in infected cells before they were exposed to IFN-gamma, indicating that other stimuli produced during infection may also regulate these genes. Following IFN-gamma treatment, none of the 127 IFN-gamma-responsive genes could be significantly induced in infected cells. Immunofluorescence assays showed at single-cell levels that infected cells, regardless of which Toxoplasma strain was used, could not be activated by IFN-gamma to up-regulate the expression of IFN regulatory factor 1, a transcription factor that is under the direct control of STAT1, whereas uninfected cells in the same culture expressed IFN regulatory factor 1 normally in response to IFN-gamma. STAT1 trafficked to the nucleus normally and indistinguishably in all uninfected and infected cells treated with IFN-gamma, indicating that the inhibitory effects of Toxoplasma infection likely occur via blocking STAT1 transcriptional activity in the nucleus. In contrast, a closely related apicomplexan, Neospora caninum, was unable to inhibit IFN-gamma-induced gene expression. A differential ability to interfere with the IFN-gamma response may, in part, account for the differences in the pathogenesis seen among Toxoplasma and Neospora parasite strains.

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          Author and article information

          Journal
          J Immunol
          Journal of immunology (Baltimore, Md. : 1950)
          The American Association of Immunologists
          0022-1767
          0022-1767
          Apr 15 2007
          : 178
          : 8
          Affiliations
          [1 ] Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
          Article
          178/8/5154
          10.4049/jimmunol.178.8.5154
          17404298
          2e75dd5a-5e2e-418b-9419-8ecccdfdc279
          History

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