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To thwart this defense,\n              <jats:italic>T. gondii<\/jats:italic>\n              secretes protein effectors hindering the host\u2019s immune response. For example,\n              <jats:italic>T. gondii<\/jats:italic>\n              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\u03b3-primed primary human fibroblasts identified MYR translocon components as crucial for parasite resistance against IFN\u03b3-driven vacuole clearance. However, these screens did not pinpoint specific MYR-dependent GRA proteins responsible for IFN\u03b3 signaling blockade, suggesting potential functional redundancy. Our study reveals that\n              <jats:italic>T. gondii<\/jats:italic>\n              depends on the MYR translocon complex to prevent parasite premature egress and host cell death in human cells stimulated with IFN\u03b3 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\u03b3 response. GRA24 and GRA28 directly influenced IFN\u03b3-driven transcription, GRA24\u2019s 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\n              <jats:italic>T. gondii<\/jats:italic>\n              , it appears that the parasite has evolved equally elaborate mechanisms to subvert IFN\u03b3 signaling, extending beyond direct interference with the JAK\/STAT1 pathway, to encompass other signaling pathways as well.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                <jats:italic>Toxoplasma gondii<\/jats:italic>\n                , an intracellular parasite, affects nearly one-third of the global human population, posing significant risks for immunocompromised patients and infants infected\n                <jats:italic>in utero<\/jats:italic>\n                . In murine models, the core mechanisms of IFN\u03b3-mediated immunity against\n                <jats:italic>T. gondii<\/jats:italic>\n                are consistently preserved, showcasing a remarkable conservation of immune defense mechanisms. In humans, the recognized restriction mechanisms vary among cell types, lacking a universally applicable mechanism. This difference underscores a significant variation in the genes employed by\n                <jats:italic>T. gondii<\/jats:italic>\n                to shield itself against the IFN\u03b3 response in human vs murine cells. Here, we identified a specific combination of four parasite-secreted effectors deployed into the host cell nucleus, disrupting IFN\u03b3 signaling. This disruption is crucial in preventing premature egress of the parasite and host cell death. Notably, this phenotype is exclusive to human cells, highlighting the intricate and unique mechanisms\n                <jats:italic>T. gondii<\/jats:italic>\n                employs to modulate host responses in the human cellular environment.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.02124-24","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T13:04:32Z","timestamp":1726664672000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["A combination of four\n            <i>Toxoplasma gondii<\/i>\n            nuclear-targeted effectors protects against interferon gamma-driven human host cell death"],"prefix":"10.1128","volume":"15","author":[{"given":"Brittany","family":"Henry","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Center for Tropical and Emerging Infectious Diseases, University of Georgia, Athens, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9799-3253","authenticated-orcid":false,"given":"Aubrey J.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Center for Tropical and Emerging Infectious Diseases, University of Georgia, Athens, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7110-0285","authenticated-orcid":false,"given":"L. 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