A Combination of Four Nuclear Targeted Effectors Protects Toxoplasma Against Interferon Gamma Driven Human Host Cell Death During Acute Infection.

Abstract

In both mice and humans, Type II interferon-gamma (IFN{gamma}) is crucial for regulation of Toxoplasma gondii (T. gondii) infection, during acute or chronic phases. To thwart this defense, T. gondii secretes protein effectors hindering the hosts immune response. For example, T. gondii relies on the MYR translocon complex to deploy soluble dense granule effectors (GRAs) into the host cell cytosol or nucleus. Recent genome-wide loss-of-function screens in IFN{gamma}-primed primary human fibroblasts identified MYR translocon components as crucial for parasite resistance against IFN{gamma} driven vacuole clearance. However, these screens did not pinpoint specific MYR-dependent GRA proteins responsible for IFN{gamma} signaling blockade, suggesting potential functional redundancy. Our study reveals that T. gondii depends on the MYR translocon complex to prevent host cell death and parasite premature egress in human cells stimulated with IFN{gamma} post-infection, a unique phenotype observed in various human cell lines but not in murine cells. Intriguingly, inhibiting parasite egress did not prevent host cell death, indicating this mechanism is distinct from those described previously. Genome-wide loss-of-function screens uncovered TgIST, GRA16, GRA24, and GRA28 as effectors necessary for a complete block of IFN{gamma} response. GRA24 and GRA28 directly influenced IFN{gamma} driven transcription, GRA24s action depended on its interaction with p38 MAPK, while GRA28 disrupted histone acetyltransferase activity of CBP/p300. Given the intricate nature of the immune response to T. gondii, it appears that the parasite has evolved equally elaborate mechanisms to subvert IFN{gamma} signaling, extending beyond direct interference with the JAK/STAT1 pathway, to encompass other signaling pathways as well.