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A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans.

机械敏感性离子通道PIEZO1中的常见多态性与人类免受严重疟疾的保护有关。

  • 影响因子:8.58
  • DOI:10.1073/pnas.1919843117
  • 作者列表:"Nguetse CN","Purington N","Ebel ER","Shakya B","Tetard M","Kremsner PG","Velavan TP","Egan ES
  • 发表时间:2020-04-21
Abstract

:Malaria caused by the apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood-brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 E756del and malaria severity among children in Gabon. We found that the E756del variant is strongly associated with protection against severe malaria in heterozygotes. In subjects with sickle cell trait, heterozygosity for PIEZO1 E756del did not confer additive protection and homozygosity was associated with an elevated risk of severe disease, suggesting an epistatic relationship between hemoglobin S and PIEZO1 E756del. Using donor blood samples, we show that red cells heterozygous for PIEZO1 E756del are not dehydrated and can support the intracellular growth of P. falciparum similar to wild-type cells. However, surface expression of the P. falciparum virulence protein PfEMP-1 was significantly reduced in infected cells heterozygous for PIEZO1 756del, a phenomenon that has been observed with other protective polymorphisms, such as hemoglobin C. Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and suggest that the mechanism of protection may be related to impaired export of P. falciparum virulence proteins.

摘要

: 由apicomplexan寄生虫恶性疟原虫引起的疟疾在整个人类历史中充当了强大的进化力量,选择了赋予对严重疾病的先天保护的红细胞多态性。最近,机械敏感性离子通道PIEZO1的功能获得突变被证明可以改善疟疾小鼠模型中疟原虫的生长、血脑屏障功能障碍和死亡率。在人类中,功能获得等位基因PIEZO1 E756del在非洲人中高度流行和富集,增加了由于疟疾而处于正选择的可能性。在这里,我们使用病例对照研究设计来测试PIEZO1 E756del与加蓬儿童疟疾严重程度之间的关联。我们发现E756del变体与杂合子中防止严重疟疾密切相关。在有镰状细胞特征的受试者中,PIEZO1 E756del的杂合性不赋予加性保护,并且纯合性与严重疾病的风险升高相关,表明血红蛋白S和PIEZO1 E756del之间存在上位关系。使用供体血液样品,我们显示压电1 E756del杂合的红细胞没有脱水,并且可以支持恶性疟原虫类似于野生型细胞的细胞内生长。然而,恶性疟原虫毒力蛋白PfEMP-1的表面表达在被感染的细胞中显著降低,该现象与其他保护性多态性一起被观察到,如血红蛋白C。我们的研究结果表明,PIEZO1是人类疟疾易感性的重要先天决定因素,并表明保护机制可能与恶性疟原虫毒力蛋白的输出受损有关。

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