A common polymorphism in the mechanosensitive ion channel <i>PIEZO1</i> is associated with protection from severe malaria in humans

Abstract

Malaria caused by the apicomplexan parasite <i>Plasmodium falciparum</i> 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 <i>PIEZO1</i> were shown to ameliorate <i>Plasmodium</i> parasite growth, blood-brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele <i>PIEZO1</i> 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 <i>PIEZO1</i> 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 <i>PIEZO1</i> 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 <i>PIEZO1</i> E756del. Using donor blood samples, we show that red cells heterozygous for <i>PIEZO1</i> E756del are not dehydrated and can support the intracellular growth of <i>P. falciparum</i> similar to wild-type cells. However, surface expression of the <i>P. falciparum</i> virulence protein PfEMP-1 was significantly reduced in infected cells heterozygous for <i>PIEZO1</i> 756del, a phenomenon that has been observed with other protective polymorphisms, such as hemoglobin C. Our findings demonstrate that <i>PIEZO1</i> is an important innate determinant of malaria susceptibility in humans and suggest that the mechanism of protection may be related to impaired export of <i>P. falciparum</i> virulence proteins.