Malaria parasite fitness in healthy human red cells is driven by common host variation

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.

恶性疟原虫疟疾寄生虫在红细胞（RBCs）内的复制会在人类中引发严重疾病，尤其是在非洲。除了少数像镰状细胞这样的有害等位基因外，宿主红细胞变异对寄生虫复制的影响在很大程度上尚未被探究。在此，我们对122名个体（大多数为非洲裔）捐献的血液进行了外显子组测序、红细胞表型分析以及寄生虫适应性检测的综合分析。在缺乏血红蛋白病或葡萄糖 - 6 - 磷酸脱氢酶缺乏症等位基因的捐献者中，包括大小、变形能力和水合状态在内的红细胞表型解释了寄生虫生长率变异的21% - 38%。此外，包括血影蛋白α链（SPTA1）、机械敏感离子通道蛋白（PIEZO1）和质膜Ca²⁺ - ATP酶4（ATP2B4）在内的14种红细胞蛋白中的非致病性多态性解释了寄生虫生长变异的45% - 70%。有趣的是，我们几乎没有观察到非洲人和欧洲人之间在这种变异上存在差异选择的证据。这些发现表明了一种模型，即适量基因中广泛存在的非致病性变异强烈调节恶性疟原虫在红细胞中的适应性。