Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood-brain barrier in cerebral malaria.

Abstract

Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum-infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)- and endothelial protein C receptor (EPCR)-binding 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-brain 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-dependent 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.

• Authors: Yvonne Adams, Rebecca W Olsen, Anja Bengtsson, Nanna Dalgaard, Mykola Zdioruk, Sanghamitra Satpathi, Prativa K Behera, Praveen K Sahu, Sean E Lawler, Klaus Qvortrup, Samuel C Wassmer, Anja T R Jensen
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 218 Issue 3 (03 01 2021) ISSN: 1540-9538 [Electronic] United States
• PMID: 33492344 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Adams et al.

Chemical References

• Endothelial Protein C Receptor
• Protein Isoforms
• Protozoan Proteins
• erythrocyte membrane protein 1, Plasmodium falciparum
• Intercellular Adhesion Molecule-1

Topics

• Adult
• Animals
• Blood-Brain Barrier (pathology)
• Endocytosis
• Endothelial Cells (metabolism, ultrastructure)
• Endothelial Protein C Receptor (metabolism)
• Erythrocytes (parasitology, pathology)
• Humans
• Intercellular Adhesion Molecule-1 (metabolism)
• Malaria, Cerebral (parasitology, pathology)
• Microvilli (metabolism)
• Models, Biological
• Molecular Docking Simulation
• Parasites (metabolism)
• Plasmodium falciparum (isolation & purification, ultrastructure)
• Protein Binding
• Protein Isoforms (metabolism)
• Protozoan Proteins (genetics)
• Rats
• Spheroids, Cellular (metabolism, pathology)