Abstract
Toxoplasma gondii is an important human and animal pathogen that causes life-threatening toxoplasmosis. Interferon-γ (IFN-γ) is critical for anti-T. gondii cell-autonomous immunity in both humans and mice. To proliferate efficiently within the hosts, virulent strains of T. gondii can suppress IFN-γ-dependent immunity. During parasite infection, it is well-characterized that various virulence effectors are secreted to transcriptionally or post-translationally target IFN-γ-inducible GTPases, which are essential for anti-parasite responses in mice. However, the role of IFN-γ-inducible GTPases in anti-T. gondii responses in human cells is controversial since they are non-functional or absent in humans. Instead, IFN-γ-induced tryptophan degradation by indole-2,3-dioxygenase (IDO) is important for the anti-T. gondii human response. To date, the T. gondii virulent mechanism targeting IDO in human cells remains elusive. Here we show that although humans possess two IDO isozymes, IDO1 and IDO2, human cells of various origins require IDO1 but not IDO2 for IFN-γ-induced cell-autonomous immunity to T. gondii. T. gondii secretes an effector TgIST to inhibit IDO1 mRNA expression. Taken together, the data suggests that T. gondii possesses virulence programs operated by TgIST to antagonize IFN-γ-induced IDO1-mediated anti-parasite cell-autonomous immunity in human cells.
Highlights
Toxoplasma gondii is an intracellular apicomplexan protozoan that has a broad range of intermediate hosts, including humans [1, 2]
IFN-γ-induced degradation of arginine by inducible NO synthase (iNOS), or of tryptophan by IDO, which consists of two members, IDO1 and IDO2, have been shown to be important for the anti-T. gondii response in mouse or human cells [18, 30, 31]
We treated HAP1 cells with a pharmacological inhibitor of iNOS known as aminoguanidine or an inhibitor of IDO known as 1-methyl-DL-tryptophan (1DL-MT), and compared the parasite numbers. 1-DL-MT but not aminoguanidine treatment abolished the IFN-γ-induced reduction of T. gondii numbers in HAP1 cells (Figure 1D), strongly suggesting the anti-T. gondii function of IDO in the human HAP1 cell line
Summary
Toxoplasma gondii is an intracellular apicomplexan protozoan that has a broad range of intermediate hosts, including humans [1, 2]. The type I cytokine interferon-γ (IFN-γ), which is produced by CD4+ T cells and natural killer cells (NK), is an essential host factor for anti-T. gondii responses in host cells [6] This is because IFN-γ activates the transcription factor STAT1 and induces the expression of hundreds of genes [7]. Atg16L1deficient murine cells are severely defective in the IFN-γ-induced clearance of T. gondii due to impaired recruitment of GBPs and IRGs to T. gondii [12, 13], suggesting the essential role of Atg16L1 in anti-T. gondii responses in mice. This parasitostatic mechanism involves nitric oxide (NO), which is produced by IFN-γ-inducible NO synthase (iNOS) [14]. The significance of these IFN-γ-inducible factors for anti-T. gondii immune responses in mice has previously been established
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