Toxoplasma gondii dysregulates IFN-gamma-inducible gene expression in human fibroblasts: insights from a genome-wide transcriptional profiling.
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.
Kim
Seon-Kyeong
SK
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Fouts
Ashley E
AE
Boothroyd
John C
JC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000502:physiology; D014122:Toxoplasma / Q000472:pathogenicity*
D000949:Histocompatibility Antigens Class II; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma