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We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)\u2013 and endothelial protein C receptor (EPCR)\u2013binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood\u2013brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1\u2013dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.<\/jats:p>","DOI":"10.1084\/jem.20201266","type":"journal-article","created":{"date-parts":[[2020,12,12]],"date-time":"2020-12-12T02:21:37Z","timestamp":1607739697000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":72,"title":["<i>Plasmodium falciparum<\/i>\n                    erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood\u2013brain barrier in cerebral malaria"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8041-6580","authenticated-orcid":true,"given":"Yvonne","family":"Adams","sequence":"first","affiliation":[{"name":"Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 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