Toxo Dysregulates IFN-{gamma}-Inducible Gene Expression in Human Fibroblasts

J Immunol. 2007 Apr 15;178(8):5154-65.

Toxoplasma gondii Dysregulates IFN-{gamma}-Inducible Gene Expression in Human Fibroblasts: Insights from a Genome-Wide Transcriptional Profiling

Kim SK, Fouts AE, Boothroyd JC.

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.

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.

PMID: 17404298 [PubMed - in process]