Toxoplasma Gondii Effectors TgIST and TgGRA15 Differentially Target Host IDO1 to Antagonize the IFN-γ-induced Anti-T. Gondii Response in Human Cells

概要

Toxoplasma is an important intracellular pathogen that causes lethal toxoplasmosis in humans and animals. Interferon-γ (IFN-γ) is critical for anti-T. gondii responses in both human and mice. Recent extensive studies using the mouse as a model organism have revealed that IFN-γ-inducible GTPases play critical roles, and also revealed that virulent T. gondii can inhibit IFN-γ-mediated host immune response. Thus, the relation between host immunity and T. gondii virulence is well established in mice. On the other hand, IFN-γ-induced anti-T. gondii responses in human is not completely clear because the IFN-γ-inducible GTPase-mediated anti-T. gondii responses may not be major in human. Therefore, T. gondii virulence strategy to resist IFN-γ-induced anti-T. gondii responses in human also largely remains unclear. Here, at first, we generate various human cells lacking IFN-γ-inducible gene, and show that IDO1 is required for IFN-γ-induced response in various types of human cells. Then, we focus on T. gondii virulence mechanisms in human cell. In this study, we focus on distinct T. gondii virulence mechanisms involving TgIST and TgGRA15 to suppress IFN-γ- dependent immunity in human cells. We generate TgIST or TgGRA15-deficient T. gondii by CRISPR/Cas9 system, and show that IDO1 mRNA induction is inhibited TgIST-dependently in various types of IFN-γ-stimulated human cells, and also show that IDO1-dependent anti-T. gondii response is inhibited TgGRA15-dependently in secondly infected cells. Taken together, we demonstrate that T. gondii possesses at least two differential virulence mechanisms targeting IDO1 by TgIST and TgGRA15 to antagonize IFN-γ- induced anti-T. gondii responses in human cells.