Common host variation drives malaria parasite fitness in healthy human red cells

The replication of Plasmodium falciparum malaria parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. The influence of host erythrocyte variation on parasite replication is largely uncharted, aside from a handful of deleterious alleles like sickle cell. Here, we integrated analyses of exome sequencing, RBC phenotyping, and parasite fitness assays on blood donated by 122 individuals, most with African ancestry. In donors lacking alleles for hemoglobinopathies or G6PD deficiency, RBC phenotypes including size, deformability, and hydration status explained 21-38% of the variation in parasite growth rate. Furthermore, non-pathogenic polymorphisms in 14 RBC proteins including SPTA1, PIEZO1, and ATP2B4 explained 45-70% of parasite growth variation. Interestingly, we observed little evidence for divergent selection on this variation between Africans and Europeans. These findings suggest a model in which widespread, non-pathogenic variation in a moderate number of genes strongly modulates P. falciparum fitness in RBCs.