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We identify distinct parasite programs associated with WHO-defined severe disease, characterized by transcriptional activation of stress-response and host\u2013interaction pathways. In contrast, invasion-linked programs were more strongly associated with parasite burden, while immune-evasion pathways showed overlapping but distinct associations with both burden and severity. GWAS and eQTL analyses revealed genetic regulation of transcriptional states, including immune-evasion variant antigen families (\n                  <jats:italic>SICAvar<\/jats:italic>\n                  and\n                  <jats:italic>kir<\/jats:italic>\n                  ) and chromatin-associated regulators. Mature gametocyte transcripts were detectable across infections, including those with low parasitaemia, indicating that transmission-stage expression occurs independently of both clinical severity and parasite density. Together, these findings show that severe\n                  <jats:italic>P. knowlesi<\/jats:italic>\n                  malaria is associated with genetically regulated parasite transcriptional programs that are not fully explained by parasite burden.\n                <\/jats:p>","DOI":"10.64898\/2026.03.22.713451","type":"posted-content","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T23:40:13Z","timestamp":1774309213000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrative genomics of\n                  <i>Plasmodium knowlesi<\/i>\n                  reveals parasite-intrinsic regulators of severe human malaria"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5171-819X","authenticated-orcid":false,"given":"Jacob A F","family":"Westaway","sequence":"first","affiliation":[{"name":"Menzies School of Health Research and Charles Darwin University, Northern Territory, Australia"},{"name":"Centre for Tropical Bioinformatics and Molecular 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Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4638-536X","authenticated-orcid":false,"given":"Sarah","family":"Auburn","sequence":"additional","affiliation":[{"name":"Menzies School of Health Research and Charles Darwin University, Northern Territory, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"William","sequence":"additional","affiliation":[{"name":"Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giri S","family":"Rajahram","sequence":"additional","affiliation":[{"name":"Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia"},{"name":"Queen Elizabeth II Hospital-Clinical Research Centre, Ministry of Health Malaysia, 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