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Severe malaria is associated with parasite binding to endothelial protein C receptor

Louise Turner1, Thomas Lavstsen, Sanne S Berger

  • 1Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. lturner@sund.ku.dk

Nature
|June 7, 2013
PubMed

Insights

Severe malaria involves Plasmodium falciparum-infected red blood cells sticking to blood vessels. Researchers found that the endothelial protein C receptor (EPCR) is the binding site for specific malaria proteins, impacting disease severity.

Area of Science:

  • Malariology
  • Immunology
  • Vascular Biology

Background:

  • Severe childhood malaria, causing ~1 million deaths annually, stems from Plasmodium falciparum-infected erythrocyte sequestration.
  • Sequestration relies on interactions between P. falciparum erythrocyte membrane protein 1 (PfEMP1) and endothelial receptors.
  • Specific PfEMP1 subtypes (DC8 and DC13) are linked to severe malaria, but their receptor was unidentified.

Purpose of the Study:

  • To identify the endothelial receptor for DC8 and DC13 PfEMP1 variants.
  • To elucidate the molecular mechanism of PfEMP1-EPCR interaction in severe malaria pathogenesis.

Main Methods:

  • Protein-protein interaction studies to identify the PfEMP1 receptor.
  • Analysis of PfEMP1 binding domains (CIDRα1) and their interaction with EPCR.
  • Investigating the functional consequences of PfEMP1 binding on protein C pathway.

Main Results:

  • Endothelial protein C receptor (EPCR) identified as the receptor for DC8 and DC13 PfEMP1.
  • The cysteine-rich interdomain region (CIDRα1) of these PfEMP1 variants mediates EPCR binding.
  • PfEMP1 binding to EPCR inhibits protein C binding, potentially disrupting anticoagulation and cytoprotective pathways.

Conclusions:

  • PfEMP1 from severe malaria parasites binds to EPCR, a key receptor in protein C-mediated cytoprotection and anticoagulation.
  • This interaction links parasite adhesion to a critical host pathway, offering insights into severe malaria pathogenesis.
  • Understanding this mechanism may guide the development of novel therapeutic strategies against severe malaria.

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