Genetic manipulation of erythrocytes: Identification and characterization of essential host cell determinants for Plasmodium infection

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Malaria is an important vector-borne infectious disease that particularly affects children in sub-Saharan Africa. The etiological agents of malaria are obligate intracellular parasites of the genus Plasmodium and attempts to control the disease have been of limited success. Many parasite deter-minants of erythrocyte infection by Plasmodium have been studied in detail. In contrast, respective host cell factors that influence parasite invasion and growth are poorly characterized. This lack in our knowledge of erythrocyte determinants of invasion is in part due to the refractoriness of red blood cells to genetic manipulation. A major advance for understanding erythrocyte determinants are recent developments in the ex vivo culture of hematopoietic stem cells and their genetic manipulation employing lentiviral transduction. Hence, it is now possible to directly examine the role of red blood cell surface proteins in Plasmodium invasion by reverse genetics. Utilizing this genetic approach, we propose to study the function of erythrocyte antigens with a focus on their impact on invasion of the erythrocyte by Plasmodium parasites. Initially, we will focus on known erythrocyte receptors of Plasmodium invasion. Building on the individual in-depth characterization of their contribution to parasite invasion, we will use double and triple depletions to define a minimal set of erythrocyte receptors that are mandatory for invasion of diverse P. falciparum strains. In parallel, we propose to identify hitherto unknown receptors for Plasmodium invasion; candidates are the well-described blood group antigens. Together these two strategies will enable the direct genetic examination of erythrocytic proteins and their contribution to malaria. They constitute a novel and innovative approach for examining essential host-parasite interactions, and can identify essential targets for the barely explored avenue of host-targeted malaria therapeutics.