title: Toxoplasma gondii clonal strains all inhibit STAT1 transcriptional activity but polymorphic effectors differentially modulate IFNγ induced gene expression and STAT1 phosphorylation.
abstract: Host defense against the parasite Toxoplasma gondii requires the cytokine interferon-gamma (IFNγ). However, Toxoplasma inhibits the host cell transcriptional response to IFNγ, which is thought to allow the parasite to establish a chronic infection. It is not known whether all strains of Toxoplasma block IFNγ-responsive transcription equally and whether this inhibition occurs solely through the modulation of STAT1 activity or whether other transcription factors are involved. We find that strains from three North American/European clonal lineages of Toxoplasma, types I, II, and III, can differentially modulate specific aspects of IFNγ signaling through the polymorphic effector proteins ROP16 and GRA15. STAT1 tyrosine phosphorylation is activated in the absence of IFNγ by the Toxoplasma kinase ROP16, but this ROP16-activated STAT1 is not transcriptionally active. Many genes induced by STAT1 can also be controlled by other transcription factors and therefore using these genes as specific readouts to determine Toxoplasma inhibition of STAT1 activity might be inappropriate. Indeed, GRA15 and ROP16 modulate the expression of subsets of IFNγ responsive genes through activation of the NF-κB/IRF1 and STAT3/6 transcription factors, respectively. However, using a stable STAT1-specific reporter cell line we show that strains from the type I, II, and III clonal lineages equally inhibit STAT1 transcriptional activity. Furthermore, all three of the clonal lineages significantly inhibit global IFNγ induced gene expression.
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Rosowski
authors.forename: Jeroen P J
authors.initials: JP
authors.lastname: Saeij
mesh_terms: D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006790:Host-Parasite Interactions / Q000235:genetics / Q000502:physiology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014122:Toxoplasma / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D014158:Transcription, Genetic
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D015800:Protozoan Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C552524:Rop16 protein, Toxoplasma gondii