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.
Highlights
The cytokine interferon-gamma (IFNc) and the transcription factor it activates, signal transducer and activator of transcription (STAT) 1, are critical to host defense against the obligate intracellular parasitic pathogen Toxoplasma gondii; mice deficient in elements of this pathway are acutely susceptible to Toxoplasma infection [1,2,3]
A Type II Strain Activates IRF1 via GRA15 and NF-kB Infection of human foreskin fibroblasts (HFF) with a type II Pru strain of Toxoplasma was previously shown to induce the expression of 46 genes that were defined as IFNc regulated [13], raising the possibility that type II strains are not as good at inhibiting IFNc induced gene expression as other clonal lineages
After 24 hours of infection, with IFNc stimulation for the last six hours, while RH(I), Pru(II), and CEP(III) infection all significantly inhibited IRF1 expression compared to uninfected cells, cells pre-infected with a Pru(II) strain had significantly higher IRF1 in their nuclei than cells pre-infected with a RH(I) strain (Fig. 1A, B)
Summary
The cytokine interferon-gamma (IFNc) and the transcription factor it activates, signal transducer and activator of transcription (STAT) 1, are critical to host defense against the obligate intracellular parasitic pathogen Toxoplasma gondii; mice deficient in elements of this pathway are acutely susceptible to Toxoplasma infection [1,2,3]. Toxoplasma has been shown to inhibit the expression of IRF1 [8,9], class II transactivator (CIITA) [7,8,9], inducible nitric oxide synthase (iNOS/NOS2) [10,11], interferon inducible GTPase 1 (IIGP1) [12], and chemokine (C-XC motif) ligand 9 (MIG/CXCL9) [12]. This inhibition occurs in a variety of cell types, including human foreskin fibroblasts (HFF), human glioblastoma cells, murine bone marrow-derived macrophages (BMDM), RAW264.7 murine macrophages, murine dendritic cells, and murine microglial cells. Microarray analyses showed that Toxoplasma infection can dysregulate the entire IFNc induced gene expression program in both HFFs [13] and BMDMs [14]
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