Pathogenic mechanisms of Plasmodium falciparum egress unveiled by a microvascular 3D blood-brain barrier model

Cerebral malaria is a severe neurovascular complication of Plasmodium falciparum with high mortality, even after treatment with effective antimalarials. A better understanding of pathogenic mechanisms could help future development of adjunctive therapies, yet limitations in current experimental models have hindered our knowledge of the disease. We developed a 3D blood-brain barrier model with enhanced barrier properties using primary brain endothelial cells, astrocytes and pericytes. Exposure to parasite egress products increased microvascular permeability, likely due to transcriptional downregulation of junctional and vascular development genes in endothelial cells. In addition, it increased the expression of ferroptosis markers, antigen presentation and type I interferon genes across all BBB cell types. Incubation with cytoadherent schizont-stage P. falciparum -infected erythrocytes induced a similar, but highly localized transcriptional shift, along with inter-endothelial gaps at sites of parasite egress, significantly increasing permeability. These findings provide key insights into the parasite-mediated mechanisms driving brain microvascular pathogenesis in cerebral malaria.