How do RIFINs and STEVORs modulate human immune cell function in malaria?

The symptoms of malaria occur when Plasmodium parasites replicate within human blood cells. The largest parasite protein family displayed on Plasmodium falciparum-infected erythrocytes contains the RIFINs and STEVORs. Recently, applicants on this award discovered that RIFINs can suppress human immune cell function by mimicking the human ligand of inhibitory immune receptor LILRB1. We have also discovered RIFINs which bind four other human inhibitory immune receptors. We now aim to determine: “How do RIFINs and STEVORs modulate human immunity during malaria?” This requires a collaborative effort, bringing together the latest tools in transgenic parasite biology, structural biology, biophysics of cell interfaces and high-throughput technology. Using these tools, we will determine how RIFINs which bind to five different inhibitory immune receptors affect survival of infected erythrocytes in the context of killing by four types of human immune cell, and will show how RIFIN-targeting antibodies modulate these effects. We will conduct high-throughput experiments to determine which RIFINs and STEVORs provide a survival advantage in the context of immune cell-mediated killing and will determine the ligand binding properties of all RIFINs and STEVORs from one parasite genome. These studies will show how RIFINs and STEVORs manipulate human immune cell function during malaria.