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Macrophages, the immune system\u2019s first responders, play a pivotal role in determining infection outcomes, yet the initial triggers shaping these complex responses remain elusive. This study unveils the earliest transcriptional shifts in a mouse macrophage-like cell line RAW264.7-\n                    <jats:italic>T. gondii<\/jats:italic>\n                    infection model. Using time-resolved transcriptomic profiling, we captured host and parasite gene expression dynamics within the critical 15\u2013120 minute window \u2014 when the host mounts its first line of defence and the parasite secures its foothold. By leveraging inactivated parasites, we disentangled responses to active invasion from general immune activation. By 60 minutes, macrophages exhibited a trend of increased suppressor of cytokine signalling expression \u2014 uniquely tied to live infection \u2014 while stress and pro-growth genes became dysregulated. Meanwhile,\n                    <jats:italic>T. gondii<\/jats:italic>\n                    responded with a slow but strategic transcriptional shift: an early increase in transcription and growth capacity, followed by a delayed activation of secreted proteins. These findings reveal a tug-of-war at the transcriptional level, where macrophages show rapid upregulation, while\n                    <jats:italic>T. gondii<\/jats:italic>\n                    employs a measured, delayed strategy to carve out its replicative niche.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0336849","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T18:22:05Z","timestamp":1764008525000},"page":"e0336849","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early upregulation of immune suppressors dominates the macrophage response to Toxoplasma gondii"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8204-5233","authenticated-orcid":true,"given":"Dominykas","family":"Murza","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filip","family":"Lastovka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3497-6329","authenticated-orcid":true,"given":"George","family":"Wood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew P.","family":"Brember","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James W.","family":"Ajioka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4384-285X","authenticated-orcid":true,"given":"Betty Y. 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