Infected erythrocytes expressing DC13 PfEMP1 differ from recombinant proteins in EPCR-binding function
Yvonne Azasi1,2,3, Gabriella Lindergard1,2, Ashfaq Ghumra1,2
1Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom.
Summary
Plasmodium falciparum-infected erythrocytes (IEs) binding to endothelial protein C receptor (EPCR) is crucial for cerebral malaria. However, IEs expressing specific Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants showed unexpected lack of EPCR binding, challenging prior findings.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Endothelial protein C receptor (EPCR) is implicated in cerebral malaria pathogenesis.
- Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants, specifically DC8 and DC13, are thought to mediate binding to EPCR.
- Previous studies mapped the PfEMP1-EPCR interaction using recombinant proteins, but in vivo studies with native PfEMP1 on infected erythrocytes (IEs) are limited.
Purpose of the Study:
- To investigate the binding of IEs expressing DC8 and DC13 PfEMP1 variants to EPCR.
- To compare the binding activity of native PfEMP1 on IEs with previously characterized recombinant PfEMP1 proteins.
- To assess the role of EPCR in IE adhesion to brain endothelial cells under static and flow conditions.
Main Methods:
- Static and flow adhesion assays were used to examine IE binding to immobilized EPCR and human brain endothelial cells.
- IEs expressing specific PfEMP1 variants (HB3var03, IT4var07, IT4var19) were utilized.
- The effect of normal human serum or plasma on IE-EPCR interactions was investigated.
Main Results:
- IEs expressing DC13 PfEMP1 variants (HB3var03, IT4var07) did not bind to immobilized EPCR, and their binding to brain endothelial cells was EPCR-independent.
- IEs expressing the DC8 variant IT4var19 bound to EPCR, but this binding was inhibited by normal human serum or plasma.
- A discrepancy was observed between the EPCR-binding activity of recombinant PfEMP1 proteins and native PfEMP1 on IEs.
Conclusions:
- The interaction between PfEMP1 on IEs and EPCR is more complex than suggested by recombinant protein studies.
- Plasma components may prevent IE-EPCR interactions under physiological conditions.
- Further research is needed to elucidate the pathophysiological significance of the PfEMP1-EPCR interaction in cerebral malaria.
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