Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria

• Published in: Cell host & microbe 2017-03, Vol.21 (3), p.403-414
• Main Authors: Lennartz, Frank, Adams, Yvonne, Bengtsson, Anja, Olsen, Rebecca W., Turner, Louise, Ndam, Nicaise T., Ecklu-Mensah, Gertrude, Moussiliou, Azizath, Ofori, Michael F., Gamain, Benoit, Lusingu, John P., Petersen, Jens E.V., Wang, Christian W., Nunes-Silva, Sofia, Jespersen, Jakob S., Lau, Clinton K.Y., Theander, Thor G., Lavstsen, Thomas, Hviid, Lars, Higgins, Matthew K., Jensen, Anja T.R.
• Format: Article
• Language: English
• Subjects: Antigens, CD - metabolism; Cell Adhesion; cerebral malaria; Computational Biology; Crystallography, X-Ray; Endothelial Protein C Receptor; EPCR; Genome, Protozoan; ICAM-1; Intercellular Adhesion Molecule-1 - metabolism; Malaria, Cerebral - parasitology; Malaria, Falciparum - parasitology; PfEMP1; Plasmodium falciparum; Plasmodium falciparum - pathogenicity; Plasmodium falciparum - physiology; Protein Binding; Protozoan Proteins - chemistry; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Receptors, Cell Surface - metabolism; Scattering, Small Angle; Sequence Analysis, DNA; Surface Plasmon Resonance; Virulence Factors - chemistry; Virulence Factors - genetics; Virulence Factors - metabolism
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2017.02.009

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. [Display omitted] •Structural basis for P. falciparum PfEMP1 binding to endothelial receptor ICAM-1defined•A sequence motif derived from structure predicts group A PfEMP1 binding to ICAM-1•These ICAM-1-binding PfEMP1s also all bind to endothelial protein C receptor (EPCR)•Expression of dual ICAM-1- and EPCR-binding PfEMP1 is associated with cerebral malaria Plasmodium falciparum-infected erythrocytes display PfEMP1 proteins that bind various endothelial receptors, including ICAM-1. Lennartz et al. structurally characterize PfEMP1 binding to ICAM-1, allowing them to identify a PfEMP1 family that simultaneously binds to both ICAM-1 and EPCR. Dual-binding PfEMP1s display stronger endothelial adhesion and are associated with cerebral malaria.