<i>Plasmodium falciparum</i>erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood–brain barrier in cerebral malaria

Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum–infected erythrocytes (IEs) to brain microvasculature, leading inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)– endothelial protein C receptor (EPCR)–binding P. falciparum parasites these symptoms, but mechanism driving pathogenesis has not been identified. Here, we used a 3D spheroid model blood–brain barrier (BBB) determine unexpected new features IEs expressing dual-receptor PfEMP1 parasite proteins. Analysis multiple lines shows that are taken up cells in an ICAM-1–dependent manner, resulting breakdown BBB swelling cells. Via ex vivo analysis postmortem tissue samples from CM patients, confirmed presence within Importantly, this discovery points ingress into endothelium as contributing factor pathology human CM.