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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Frank Lennartz
  • Anja Bengtsson
  • Nicaise T Ndam
  • Gertrude Delali Ecklu-Mensah
  • Azizath Moussiliou
  • Michael F Ofori
  • Benoit Gamain
  • John P. Lusingu
  • Jens Emil Vang Petersen
  • Sofia Nunes-Silva
  • Clinton K Y Lau
  • Matthew K Higgins

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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