Cerebral malaria is a deadly complication of Plasmodium falciparum infection that is associated with the massive accumulation of infected erythrocytes in cerebral microvasculature. Parasite binding is mediated by the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. Recently, we discovered that parasites expressing DC8 and DC13 PfEMP1 are associated with cerebral malaria and showed that they bind to endothelial protein C receptor (EPCR) via the cysteine-rich interdomain region (CIDR) domain in PfEMP1. The finding that DC8 and DC13 PfEMP1 bind EPCR has important implications for cerebral malaria pathogenesis. EPCR is a receptor for activated protein C and plays a key role in regulating coagulation and endothelial barrier properties. These findings suggest there may be causal links between parasite cytoadhesion and microvascular pathology, such as a blockade of the protein C-EPCR interaction by DC8 or DC13-expressing infected erythrocytes. While this mechanism provides an appealing explanation for many of the pathophysiological correlates of cerebral malaria, a number of critical questions remain unanswered including to what extent DC8 and DC13 PfEMP1 inhibit EPCR function and identifying the combination of host receptors mediating cerebral binding. In this project, we will: 1. Determine if EPCR-binding parasites inhibit the protein C-EPCR interaction, 2. Determine if EPCR-binding parasites affect the cytoprotective and pro-barrier function of EPCR on endothelial cells and 3. Determine the combination of host receptors that act in concert with EPCR to mediate high affinity binding of DC8 variants to brain endothelial cells. This project will characterize the molecular mechanisms by which P. falciparum-infected erythrocytes adhere to brain endothelial cells, shed light on the pathogenic mechanisms associated with cerebral malaria, and may suggest anti-adhesive strategies or new treatment options to improve cerebral malaria outcomes.

Public Health Relevance

The project described here will increase our understanding of how P. falciparum infected erythrocytes sequester in the brain and cause the deadly malaria complication cerebral malaria. Determining the molecular mechanisms of cerebral binding may lead to interventions to treat cerebral malaria and improve patient outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI114766-01A1
Application #
8964454
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2015-06-24
Project End
2020-05-31
Budget Start
2015-06-24
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
$493,105
Indirect Cost
$232,203
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Brazier, Andrew J; Avril, Marion; Bernabeu, Maria et al. (2017) Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins. mSphere 2:
Kessler, Anne; Dankwa, Selasi; Bernabeu, Maria et al. (2017) Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. Cell Host Microbe 22:601-614.e5
Avril, Marion; Bernabeu, Maria; Benjamin, Maxwell et al. (2016) Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum-Infected Erythrocytes to Endothelial Cells. MBio 7:
Gillrie, Mark R; Renaux, Bernard; Russell-Goldman, Eleanor et al. (2016) Thrombin Cleavage of Plasmodium falciparum Erythrocyte Membrane Protein 1 Inhibits Cytoadherence. MBio 7: