Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

Cell Host Microbe. 2017 Nov 8;22(5):601-614.e5. doi: 10.1016/j.chom.2017.09.009. Epub 2017 Oct 26.


Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling.

Keywords: EPCR; PfEMP1; Plasmodium falciparum; brain swelling; cerebral malaria; var.

MeSH terms

  • Brain / parasitology
  • Brain Edema / metabolism*
  • Brain Edema / parasitology
  • Cell Adhesion
  • Child
  • Child, Preschool
  • Endothelial Protein C Receptor / metabolism*
  • Female
  • Humans
  • Infant
  • Malaria, Cerebral / metabolism*
  • Malaria, Cerebral / parasitology
  • Malaria, Falciparum / metabolism
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / physiopathology
  • Malawi
  • Male
  • Neoplasm Proteins / metabolism*
  • Plasmodium falciparum / metabolism*
  • Plasmodium falciparum / pathogenicity*
  • Protein Binding
  • Protein Domains
  • Protozoan Proteins / metabolism
  • Receptors, Cell Surface / metabolism*


  • Endothelial Protein C Receptor
  • Neoplasm Proteins
  • PROCR protein, human
  • Protozoan Proteins
  • Receptors, Cell Surface
  • epithelial membrane protein-1