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Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.

Original publication

DOI

10.1016/j.chom.2017.02.009

Type

Journal article

Journal

Cell Host Microbe

Publication Date

08/03/2017

Volume

21

Pages

403 - 414

Keywords

EPCR, ICAM-1, PfEMP1, Plasmodium falciparum, cerebral malaria, Antigens, CD, Cell Adhesion, Computational Biology, Crystallography, X-Ray, Endothelial Protein C Receptor, Genome, Protozoan, Intercellular Adhesion Molecule-1, Malaria, Cerebral, Malaria, Falciparum, Plasmodium falciparum, Protein Binding, Protozoan Proteins, Receptors, Cell Surface, Scattering, Small Angle, Sequence Analysis, DNA, Surface Plasmon Resonance, Virulence Factors