Application of novel stem cell technologies to understand the impact of human genetic variation on malaria infection

Malaria is a world-wide disease with half the population of the world at risk of infection and causing over half a million deaths every year. The parasite has a complex life cycle but the blood cycle stage, when it multiplies in red blood cells, is the main cause of clinical symptoms. During the blood cycle, the parasite utilises many host proteins and factors to invade, survive and proliferate in the cells. However the anucleate nature of red blood cells makes them inaccessible to genetic tools, so studying erythrocyte proteins involved in malaria invasion and development is particularly difficult. To overcome this limitation, I developed a protocol to differentiate red blood cells from human stem cells that allows manipulation of erythroid genes in the pluripotent nucleated state and generate 'custom made' red blood cells. These are then challenged with the parasite in a specialised assay to assess the effect of the manipulation on infection. The use of induced Pluripotent Stem Cells opens the opportunity to examine complex traits and patient-derived cell lines to assess genomic background in the context of the infection.