Febrile Temperature Augments Ring-stage Plasmodium falciparum Adhesion to Brain Endothelial Cells

Sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the microvasculature is a major virulence determinant. While the sequestration of mature stage parasites (trophozoite and schizonts) to vascular endothelium is well established, the conditions that promote ring-stage IE sequestration are less understood. Here, we observed in ring-stage parasites that febrile exposure increased transcript levels of several exported parasite genes involved in the trafficking of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) ligand responsible for adherence to the endothelium of blood vessels. Furthermore, it accelerated PfEMP1 surface display in ring-stage IEs, leading to a 2-fold increase in their binding in a perfusable 3D human brain microvessel model. Additionally, we observed that parasite exposure enhances the binding of uninfected erythrocytes in 3D brain microvessels. These findings suggest a complex interplay between fever and parasite biomass in the pathogenesis of cerebral malaria.