Stem Cell Technology Provides Novel Tools to Understand the Impact of Human Variation on Malaria

Plasmodium falciparum parasites have a complex life cycle, but the most clinically relevant stage of the disease is the invasion of erythrocytes and the proliferation of the parasite in the blood. The influence of human genetic traits on malaria has been known for a long time, however understanding the role of the proteins involved is hampered by the anuclear nature of erythrocytes that makes them inaccessible to genetic tools. Here we overcome this limitation with a differentiation protocol to derive erythroid cells in- vitro from a diversity of human stem cells and an adaptation of flow cytometry to detect hemozoin. We combine this strategy with genome editing to show that deletion of basigin ablates invasion while deletion of ATP2B4 has a minor effect and that erythroid cells from reprogrammed patient-derived HbBart α-thalassemia samples poorly support infection. This approach offers vast potential for understanding the impact human polymorphisms on malaria.