Toxoplasma gondii Clonal Strains All Inhibit STAT1 Transcriptional Activity but Polymorphic Effectors Differentially Modulate IFN gamma Induced Gene

Host defense against the parasite Toxoplasma gondii requires the cytokine interferon-gamma (IFNc). However, Toxoplasma inhibits the host cell transcriptional response to IFNc, which is thought to allow the parasite to establish a chronic infection. It is not known whether all strains of Toxoplasma block IFNc-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 IFNc signaling through the polymorphic effector proteins ROP16 and GRA15. STAT1 tyrosine phosphorylation is activated in the absence of IFNc 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 IFNc responsive genes through activation of the NF-kB/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 IFNc induced gene expression. Citation: Rosowski EE, Saeij JPJ (2012) Toxoplasma gondii Clonal Strains All Inhibit STAT1 Transcriptional Activity but Polymorphic Effectors Differentially Modulate IFNc Induced Gene Expression and STAT1 Phosphorylation. PLoS ONE 7(12): e51448. doi:10.1371/journal.pone.0051448 Editor: Ira Blader, University of Oklahoma Health Sciences Center, United States of America Received August 10, 2012; Accepted November 1, 2012; Published December 11, 2012 Copyright: 2012 Rosowski, Saeij. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: J. Saeij was supported by National Institutes of Health R01-AI080621 and by a Scientist Development Grant from the American Heart Association (0835099N). E. Rosowski was supported by a pre-doctoral grant in the Biological Sciences (5-T32GM007287-33) and the Cleo and Paul Schimmel Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]