Infected erythrocytes expressing DC13 PfEMP1 differ from recombinant proteins in EPCR-binding function

Yvonne Azasi, Gabriella Lindergard, Ashfaq Ghumra, Jianbing Mu, Louis H Miller, J Alexandra Rowe

Research output: Contribution to journalArticlepeer-review

Abstract

Recent advances have identified a new paradigm for cerebral malaria pathogenesis in which endothelial protein C receptor (EPCR) is a major host receptor for sequestration ofPlasmodium falciparum-infected erythrocytes (IEs) in the brain and other vital organs. The parasite adhesins that bind EPCR are members of the IE variant surface antigen familyPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) containing specific adhesion domains called domain cassette (DC) 8 and DC13. The binding interaction site between PfEMP1 and EPCR has been mapped by biophysical and crystallography studies using recombinant proteins. However, studies examining the interaction of native PfEMP1 on the IE surface with EPCR are few. We aimed to study binding to EPCR by IEs expressing DC8 and DC13 PfEMP1 variants whose recombinant proteins have been used in key prior functional and structural studies. IE binding to EPCR immobilized on plastic and on human brain endothelial cells was examined in static and flow adhesion assays. Unexpectedly, we found that IEs expressing the DC13 PfEMP1 variant HB3var03 or IT4var07 did not bind to EPCR on plastic and the binding of these variants to brain endothelial cells was not dependent on EPCR. IEs expressing the DC8 variant IT4var19 did bind to EPCR, but this interaction was inhibited if normal human serum or plasma was present, raising the possibility that IE-EPCR interaction may be prevented by plasma components under physiological conditions. These data highlight a discrepancy in EPCR-binding activity between PfEMP1 recombinant proteins and IEs, and indicate the critical need for further research to understand the pathophysiological significance of the PfEMP1-EPCR interaction.

Original languageEnglish
Pages (from-to)1063-1068
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume115
Issue number5
Early online date16 Jan 2018
DOIs
Publication statusPublished - 30 Jan 2018

Keywords

  • cell adhesion
  • malaria
  • EPCR
  • PfEMP1
  • Endothelium

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