Identification of parasite erythrocyte membrane antigens specific to cerebral malaria and severe malarial anemia pathogenesis

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PROJECT SUMMARY Plasmodium falciparum is primarily responsible for severe malaria, including cerebral malaria and severe malarial anemia. Malaria parasite variant surface antigens (VSAs) are parasite proteins displayed on the surface of infected erythrocytes, facilitating cytoadhesion and sequestration by binding endothelial receptors in the host vasculature. VSAs play a critical role in pathogenesis, and the expression of VSAs subclasses that bind specific host receptors has been associated with severe malaria. However, the progression from mild to severe disease, including to the particular severe disease syndrome, is not completely understood. Identifying which malaria parasite proteins are important in the development of specific severe malarial syndromes will be crucial to develop a vaccine against severe malarial disease. Plasmodium falciparum erythrocyte membrane protein-1 antigens (PfEMP1s) are the most well-characterized VSA family. The var gene family encodes PfEMP1s, with an estimated 40-60 var genes per parasite genome. VSAs such as PfEMP1 bind to host endothelial receptors, including intercellular adhesion molecule-1 (ICAM-1), CD36, and endothelial protein C receptor (EPCR), thereby preventing immune clearance of infected erythrocytes. Identification of PfEMP1s at the protein level has been hindered by the lack of sequence data to identify peptides specific to particular PfEMP1s in clinical infections. RNA sequencing and subsequent proteomic profiling of the PfEMP1s on the surface of infected erythrocytes from the same clinical infection enables an evaluation of expression at both the gene and protein level to identify PfEMP1s specific to cerebral malaria and severe malarial anemia. Using samples from a case-control study in Mali, West Africa that compared cases of severe malaria to matched controls with uncomplicated malaria, the candidate will determine the association of the expression of PfEMP1s at the gene (Aim 1) and protein level (Aim 2). Identification of the PfEMP1s specific to severe malarial anemia and to cerebral malaria will shed light on the pathogenesis of severe disease and inform studies to detect gaps in immunity to PfEMP1s identified from clinical infections. This work will provide the candidate with valuable skills in the fields of transcriptomics, proteomics, and bioinformatics that will prepare her for a career as a 21st century epidemiologist and independent academic researcher.