FIG 8.

Intersection of IFN-STAT1 pathways and Toxoplasma. IFN-β and IFN-γ activate the expression of downstream target genes through ISGF3 and STAT1 homodimer complexes, respectively. The activation pathways of these cytokines are outlined. In a cell preinfected with Toxoplasma, the STAT1-mediated expression of both IFN-γ- and IFN-β-induced target genes is inhibited. We have measured multiple steps of these pathways and indicate here whether each step is inhibited by Toxoplasma infection or still occurs in a Toxoplasma-infected cell. Arrows indicate activation, inhibitory arrows indicate negative regulation, an “X” indicates steps which do not occur in Toxoplasma-infected cells, and a check mark indicates steps that do still occur in Toxoplasma-infected cells. We find that the Toxoplasma effector responsible for the inhibition of STAT1 activity and the expression of IFN-γ primary response genes is unlikely to be a protein secreted from the Toxoplasma rhoptry organelle prior to invasion. Although Toxoplasma infection induces the expression of SOCS family proteins, which negatively regulate JAK/STAT activation, this induction is not necessary for Toxoplasma to inhibit STAT1-mediated gene expression. We find that Toxoplasma infection inhibits the release of STAT1 from DNA, inhibiting downstream STAT1 recycling and further rounds of transcriptional activation.