Plasmodium falciparum Adhesion on Human Brain Microvascular Endothelial Cells Involves Transmigration-Like Cup Formation and Induces Opening of Intercellular Junctions

Abstract

Cerebral malaria, a major cause of death during malaria infection, is characterised by the sequestration of infected red blood cells (IRBC) in brain microvessels. Most of the molecules implicated in the adhesion of IRBC on endothelial cells (EC) are already described; however, the structure of the IRBC/EC junction and the impact of this adhesion on the EC are poorly understood. We analysed this interaction using human brain microvascular EC monolayers co-cultured with IRBC. Our study demonstrates the transfer of material from the IRBC to the brain EC plasma membrane in a trogocytosis-like process, followed by a TNF-enhanced IRBC engulfing process. Upon IRBC/EC binding, parasite antigens are transferred to early endosomes in the EC, in a cytoskeleton-dependent process. This is associated with the opening of the intercellular junctions. The transfer of IRBC antigens can thus transform EC into a target for the immune response and contribute to the profound EC alterations, including peri-vascular oedema, associated with cerebral malaria. Cerebral malaria, a major cause of death during malaria infection, is characterised by the sequestration of infected red blood cells (IRBC) in brain microvessels. This study describes the interactions between plasmodium infected red blood cell and human brain endothelial cells. It highlights the activation of a trogocytosis-like mechanism followed by an engulfment of the infected red blood cells by endothelial cells (EC). This transfer concerns up to 20% of the IRBC cocultured with EC. This means that the parasite infected erythrocyte can mimic the leukocytes interaction with endothelial cells. This process is associated with i) a transfer of malaria antigens to the EC which can inappropriately activate the immune system and ii) an opening of the intercellular junctions, which can trigger blood-brain-barrier leakage during cerebral malaria. This transfer of IRBC antigens can thus transform EC into a target for the immune response and contribute to cerebral malaria pathogenesis.