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Toxoplasma gondii effector TgIST blocks type I interferon signaling to promote infection

Significance Toxoplasma gondii infects a wide range of animals, including humans, where it can form chronic persistent infections for the life of the host. We demonstrate that the parasite T. gondii secretes an effector protein called TgIST that traffics to the host cell nucleus, binds to STAT1/STAT2 heterodimers, and blocks signaling through type I interferon (IFN). TgIST globally blocks induction of IFN-stimulated genes normally up-regulated by IFN-β, including those involved in innate defense pathways. Type I IFN is important for control of chronic infection by T. gondii in the central nervous system, and the ability of the parasite to modulate this pathway contributes to chronic persistence. In contrast to the importance of type II interferon-γ (IFN-γ) in control of toxoplasmosis, the role of type I IFN is less clear. We demonstrate here that TgIST, a secreted effector previously implicated in blocking type II IFN-γ signaling, also blocked IFN-β responses by inhibiting STAT1/STAT2-mediated transcription in infected cells. Consistent with a role for type I IFN in cell intrinsic control, ∆Tgist mutants were more susceptible to growth inhibition by murine and human macrophages activated with IFN-β. Additionally, type I IFN was important for production of IFN-γ by natural killer (NK) cells and recruitment of inflammatory monocytes at the site of infection. Mice lacking type I IFN receptors (Ifnar1−/−) showed increased mortality following infection with wild-type parasites and decreased virulence of ∆Tgist parasites was restored in Ifnar1−/− mice. The findings highlight the importance of type I IFN in control of toxoplasmosis and illuminate a parasite mechanism to counteract the effects of both type I and II IFN-mediated host defenses.