Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria

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Frank Lennartz, Yvonne Adams, Anja Bengtsson, Rebecca Wendelboe Olsen, Louise Turner, Nicaise T Ndam, Gertrude Delali Ecklu-Mensah, Azizath Moussiliou, Michael F Ofori, Benoit Gamain, John P. Lusingu, Jens Emil Vang Petersen, Christian William Wang, Sofia Nunes-Silva, Jakob Schmidt Jespersen, Clinton K Y Lau, Thor Grundtvig Theander, Thomas Lavstsen, Lars Hviid, Matthew K Higgins & 1 more Anja Tatiana Ramstedt Jensen

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 languageEnglish
JournalCell Host & Microbe
Issue number3
Pages (from-to)403-414
Number of pages12
Publication statusPublished - 8 Mar 2017

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