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Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant
Jens E V Petersen1, Eveline A M Bouwens, Ibai Tamayo
1Jens E. V. Petersen, Centre for Medical Parasitology, Dept. of International Health, Immunology & Microbiology, University of Copenhagen and Dept. of Infectious Diseases, Rigshospitalet, 1014 Copenhagen, Denmark, Tel.: +45 35327549, Fax: +45 35327851,
Abstract:
The Endothelial Protein C receptor (EPCR) is essential for the anticoagulant and cytoprotective functions of the Protein C (PC) system. Selected variants of the malaria parasite protein, Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) associated with severe malaria, including cerebral malaria, specifically target EPCR on vascular endothelial cells. Here, we examine the cellular response to PfEMP1 engagement to elucidate its role in malaria pathogenesis. Binding of the CIDRα1.1 domain of PfEMP1 to EPCR obstructed activated PC (APC) binding to EPCR and induced a loss of cellular EPCR functions. CIDRα1.1 severely impaired endothelial PC activation and effectively blocked APC-mediated activation of protease-activated receptor-1 (PAR1) and associated barrier protective effects of APC on endothelial cells. A soluble EPCR variant (E86A-sEPCR) bound CIDRα1.1 with high affinity and did not interfere with (A)PC binding to cellular EPCR. E86A-sEPCR used as a decoy to capture PfEMP1, permitted normal PC activation on endothelial cells, normal barrier protective effects of APC, and greatly reduced cytoadhesion of infected erythrocytes to brain endothelial cells. These data imply important contributions of PfEMP1-induced protein C pathway defects in the pathogenesis of severe malaria. Furthermore, the E86A-sEPCR decoy provides a proof-of-principle strategy for the development of novel adjunct therapies for severe malaria.
Insights
Malaria parasite proteins (PfEMP1) target EPCR, disrupting the Protein C system and causing severe malaria. A decoy EPCR variant (E86A-sEPCR) blocked PfEMP1, restoring normal function and reducing infected cell adhesion, offering a potential therapy.
Area of Science:
- Vascular biology
- Infectious disease
- Hematology
Background:
- Endothelial Protein C receptor (EPCR) is crucial for the Protein C (PC) system's anticoagulant and cytoprotective roles.
- Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) variants linked to severe malaria target EPCR on endothelial cells.
Purpose of the Study:
- To investigate the cellular response to PfEMP1 binding to EPCR and its role in malaria pathogenesis.
- To evaluate a soluble EPCR variant (E86A-sEPCR) as a therapeutic decoy against PfEMP1.
Main Methods:
- Studied the interaction between PfEMP1's CIDRα1.1 domain and EPCR.
- Assessed the impact of this interaction on Protein C activation and PAR1 signaling.
- Utilized E86A-sEPCR as a decoy to capture PfEMP1 and observed its effects on endothelial cells and infected erythrocyte adhesion.
Main Results:
- PfEMP1's CIDRα1.1 domain binding to EPCR blocked activated PC (APC) binding and impaired EPCR functions.
- This interaction inhibited endothelial PC activation and blocked APC-mediated PAR1 activation and barrier protection.
- E86A-sEPCR effectively captured PfEMP1, restored normal PC activation and APC barrier effects, and reduced infected erythrocyte adhesion to brain endothelial cells.
Conclusions:
- PfEMP1-induced defects in the Protein C pathway significantly contribute to severe malaria pathogenesis.
- The E86A-sEPCR decoy represents a promising strategy for developing novel adjunct therapies for severe malaria.
