Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.

中文翻译：

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非洲人群中常见的PIEZO1等位基因导致RBC脱水并减轻疟原虫感染。

遗传性干细胞增多症被认为是一种罕见的遗传疾病，其特征是红细胞（RBC）脱水并伴有轻度溶血。RBC脱水与减少体外疟原虫感染有关；但是，RBC脱水在体内预防疟疾中的作用尚不清楚。遗传性干细胞增多症的大多数病例都与机械激活的离子通道PIEZO1中的功能获得性突变有关。我们设计了遗传性干细胞增多症的小鼠模型，结果表明，由于Piezo1在RBC和T细胞中的作用，疟原虫感染未能在这些小鼠中引起实验性脑疟疾。值得注意的是，我们确定了一种新型的人类功能获得性PIEZO1等位基因E756del，存在于三分之一的非洲人口中。来自携带该等位基因的个体的RBC脱水并在体外显示出减少的疟原虫感染。