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.

中文翻译：

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常见宿主变异驱动健康人类红细胞中的疟疾寄生虫适应

恶性疟原虫疟疾寄生虫在红细胞（RBC）中的复制导致人类特别是非洲的严重疾病。除了镰状细胞等少数有害等位基因，宿主红细胞变异对寄生虫复制的影响在很大程度上尚不清楚。在这里，我们对122位个体（大多数是非洲血统）捐赠的血液进行了外显子组测序，RBC表型分析和寄生虫适应性分析的综合分析。在缺乏血红蛋白病或G6PD缺乏等位基因的供体中，RBC表型（包括大小，可变形性和水合状态）解释了寄生虫生长率变化的21-38％。此外，包括SPTA1，PIEZO1和ATP2B4在内的14种RBC蛋白的非致病性多态性解释了45-70％的寄生虫生长变化。有趣的是，我们几乎没有证据表明在非洲人和欧洲人之间的这种差异上有不同的选择。这些发现提示了一个模型，其中中等数量基因的广泛，非致病性变异强烈调节红细胞中的恶性疟原虫适应性。