{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:10:13Z","timestamp":1778818213474,"version":"3.51.4"},"reference-count":81,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,5,14]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Malaria, caused by Plasmodium parasites, has a worldwide disease burden of over 250 million cases and \u223c600\u2009000 deaths annually. A leading cause of malaria-associated mortality and morbidity is cerebral malaria (CM). Platelets mediate CM pathogenesis, although the exact mechanisms remain largely unknown. We examined whether the mechanistic target of rapamycin (mTOR) pathway in platelets contributes to malaria pathogenesis. Our results demonstrate activation of the mTOR pathway in platelets ex vivo after coincubation with Plasmodium falciparum\u2013infected red blood cells and in vivo in Plasmodium berghei ANKA (PbA)\u2013infected mice. When mTOR was specifically deleted in platelets (mTORplt\u2212\/\u2212), mice with experimental CM (ECM) had significantly increased survival. Survival differences were independent of parasitemia and thrombocytopenia. PbA-infected mTORplt\u2212\/\u2212 mice exhibited significantly reduced platelet deposition in the brain, resulting in improved cerebral blood flow and reduced brain vascular permeability. Plasma heme levels, generated during malaria, correlated significantly with intracerebral platelet accumulation in the PbA-infected mTORplt+\/+ mice but not in PbA-infected mTORplt\u2212\/\u2212 mice. In vitro experiments demonstrated that heme activates platelet mTOR downstream of immunoreceptor tyrosine-based activation motif (ITAM) signaling, predominantly through CLEC-2 (C-type lectin-like receptor 2). Blockage of heme-induced platelet activation with cobalt protoporphyrin significantly reduced platelet mTOR activation and decreased ECM-associated mortality. In conclusion, our findings demonstrate that platelet mTOR amplifies platelet activation responses induced by heme and deletion of platelet mTOR reduces platelet deposition in the brain, which we propose impedes symptomatic disease progression and malaria-associated mortality.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025030841","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T16:31:50Z","timestamp":1769445110000},"page":"2388-2401","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Heme-induced ITAM signaling exacerbates malaria-associated neuropathogenesis through activation of platelet mTOR"],"prefix":"10.1182","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-9723","authenticated-orcid":false,"given":"Irina","family":"Portier","sequence":"first","affiliation":[{"name":"1Department of Emergency Medicine, Washington University, St Louis, MO"},{"name":"2Molecular Medicine Program, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1442-3568","authenticated-orcid":false,"given":"Frederik","family":"Denorme","sequence":"additional","affiliation":[{"name":"1Department of Emergency Medicine, Washington University, St Louis, MO"},{"name":"2Molecular Medicine Program, University of Utah, Salt Lake City, UT"},{"name":"3Department of Veterinary Sciences, Faculty of Biomedical, Pharmaceutical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neal D.","family":"Tolley","sequence":"additional","affiliation":[{"name":"2Molecular Medicine Program, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Kosaka","sequence":"additional","affiliation":[{"name":"2Molecular Medicine Program, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3973-3183","authenticated-orcid":false,"given":"Izabella","family":"Andrianova","sequence":"additional","affiliation":[{"name":"1Department of Emergency Medicine, Washington University, St Louis, MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-3042","authenticated-orcid":false,"given":"Paul A.","family":"Sigala","sequence":"additional","affiliation":[{"name":"4Department of Biochemistry, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0620-3944","authenticated-orcid":false,"given":"Tracey J.","family":"Lamb","sequence":"additional","affiliation":[{"name":"5Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy A.","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"2Molecular Medicine Program, University of Utah, Salt Lake City, UT"},{"name":"6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0763-3578","authenticated-orcid":false,"given":"Hugo C.","family":"Castro-Faria-Neto","sequence":"additional","affiliation":[{"name":"7Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig N.","family":"Morrell","sequence":"additional","affiliation":[{"name":"8Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew T.","family":"Rondina","sequence":"additional","affiliation":[{"name":"2Molecular Medicine Program, University of Utah, Salt Lake City, UT"},{"name":"5Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT"},{"name":"9Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, The University of Utah, Salt Lake City, UT"},{"name":"10Department of Internal Medicine and Geriatric Research, Education, and Clinical Center, George E. 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