Malaria caused by Plasmodium falciparum is one of the most important infectious diseases of humankind. Each year there is an estimated 300-660 million episodes of clinical P. falciparum malaria and 1-2 million will die from the infection. In P. falciparum, the family of var genes encodes erythrocyte membrane proteins (PfEMPI), which act as virulence factors responsible for both antigenic variation and binding of infected erythrocytes to endothelium. Each parasite genome encodes approximately 60 PfEMPI proteins that differ between parasite strains and bind different host receptors. Severe malaria occurs when infected erythrocytes sequester in brain or placenta. The specific hypothesis behind the proposed research is that particular adhesive types may predispose to severe malaria because of their binding tropism. This study will determine the binding properties of PfEMPI proteins and how they affect infected erythrocyte selectivity for different micro-vascular endothelial cells. PfEMPI binding will be studied from a well characterized parasite isolate that has been adapted to grow in the laboratory. Parasite lines expressing specific PfEMPI variants will be generated by limited dilution cloning or by selection on different host receptors. Real-time PCR approaches with gene-specific primers to the family of var genes will be used to define the var genes expressed in the various lines. The specific adhesion properties of each PfEMPI protein will be determined by characterizing infected erythrocyte adhesion against an extensive panel of host receptors and micro-vascular endothelial cells. These studies will contribute to a detailed characterization of the cytoadhesive properties of a parasite and enable a greater understanding of the molecular basis of malaria pathogenesis. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Seattle Biomedical Research Institute
United States
Zip Code
Brazier, Andrew J; Avril, Marion; Bernabeu, Maria et al. (2017) Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins. mSphere 2:
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; Avril, Marion; Brazier, Andrew J et al. (2015) Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial pathogenesis. Cell Microbiol 17:1883-99
Sampath, Sowmya; Brazier, Andrew Jay; Avril, Marion et al. (2015) Plasmodium falciparum adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor. Cell Microbiol 17:1868-82
Smith, Joseph D (2014) The role of PfEMP1 adhesion domain classification in Plasmodium falciparum pathogenesis research. Mol Biochem Parasitol 195:82-7
Avril, Marion; Brazier, Andrew J; Melcher, Martin et al. (2013) DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells. PLoS Pathog 9:e1003430
Turner, Louise; Lavstsen, Thomas; Berger, Sanne S et al. (2013) Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498:502-5
Herricks, Thurston; Avril, Marion; Janes, Joel et al. (2013) Clonal variants of Plasmodium falciparum exhibit a narrow range of rolling velocities to host receptor CD36 under dynamic flow conditions. Eukaryot Cell 12:1490-8
Smith, Joseph D; Rowe, J Alexandra; Higgins, Matthew K et al. (2013) Malaria's deadly grip: cytoadhesion of Plasmodium falciparum-infected erythrocytes. Cell Microbiol 15:1976-83
McMillan, Paul J; Millet, Coralie; Batinovic, Steven et al. (2013) Spatial and temporal mapping of the PfEMP1 export pathway in Plasmodium falciparum. Cell Microbiol 15:1401-18

Showing the most recent 10 out of 26 publications