Plasmodium falciparum extracellular vesicles in malaria pathogenesis and immunity (360G-Wellcome-209289_A_17_Z)

Plasmodium falciparum causes disease by infecting erythrocytes and by transferring parasite-derived effectors to non-infected erythrocytes (non-IEs), altering their physical properties. The parasites also impact other cells of the circulatory system inducing inflammation. These parasite-host interactions are key to the pathogenesis of severe malaria but little is known about how parasite-derived effectors are transferred to non-infected cells. Secreted extracellular vesicles play an important role in intercellular interactions in other systems, and could be an overlooked master regulator in malaria, but little is known about P. falciparum extracellular vesicles (PfEVs). However, I have established a protocol for isolating PfEVs from clinical isolates. Proteome analysis of one revealed that PfEVs contain erythrocyte-adhesive and exported parasite proteins implicated in rigidifying erythrocytes. I hypothesize that: 1) PfEVs transfer effectors from parasites to host cells including non-IEs and 2) antibodies can neutralise PfEVs and protect against disease. To test this, I will use clinical isolates from children with severe and uncomplicated malaria to 1) describe the protein and RNA content of PfEVs, 2) investigate the impact of PfEVs on non-IEs and immune cells and 3) evaluate the protective role of anti-PfEV antibodies against severe disease.