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

Significance

The clinical presentation of Plasmodium falciparum malaria as severe versus uncomplicated is influenced by host genetic factors. Recently, a gain-of-function mutation in the mechanosensitive ion channel PIEZO1 was shown to protect mice against cerebral malaria, but its role in human malaria is unknown. Here we investigated a common PIEZO1 variant that encodes a mild gain-of-function mutant in human erythrocytes, and show that it is associated with malaria protection in Gabonese children. We found an epistatic relationship between PIEZO1 E756del and the sickle cell trait. While parasite growth and cell hydration were normal, surface expression of PfEMP-1 was reduced in the mutant cells. Understanding the link between common PIEZO1 variants and malaria susceptibility may yield new therapies for malaria.

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.