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. 2020 Apr 21;117(16):9074-9081.
doi: 10.1073/pnas.1919843117. Epub 2020 Apr 7.

A Common Polymorphism in the Mechanosensitive Ion Channel PIEZO1 Is Associated With Protection From Severe Malaria in Humans

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Free PMC article

A Common Polymorphism in the Mechanosensitive Ion Channel PIEZO1 Is Associated With Protection From Severe Malaria in Humans

Christian N Nguetse et al. Proc Natl Acad Sci U S A. .
Free PMC article

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.

Keywords: PIEZO1; genetic association study; malaria.

Conflict of interest statement

The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.
Association of malaria severity with PIEZO1 and hemoglobin genotypes. Estimated probability of severe malaria extracted from the model presented in Table 2 by (A) PIEZO1 E756 genotype and (B) hemoglobin beta genotype. P values for pairwise differences in PIEZO1 were calculated using Tukey’s HSD post hoc test. Model adjusted for age, sex, and study.
Fig. 2.
Fig. 2.
Association between PIEZO1 and malaria severity by hemoglobin type. n.s., not statistically significant. A Bayesian logistic regression model was fit to malaria severity status as a function of hemoglobin type, PIEZO1, and their interaction. Overall interaction effect is P = 0.08. P values for pairwise differences between PIEZO1 within each hemoglobin type were calculated using Tukey’s HSD post hoc test. Model also adjusted for age, sex, and study. The Hosmer–Lemeshow goodness-of-fit test suggested the model fit was appropriate (X2 = 6.03, P value = 0.64). n.s., not significant.
Fig. 3.
Fig. 3.
Characterization of PIEZO1 E756del RBCs for P. falciparum and dehydration phenotypes. (A) Growth of P. falciparum strain 3D7 or W2mef in wild-type (n = 4) or E756del heterozygous (n = 5) RBCs over two cycles of reinvasion. PMR, parasite multiplication rate relative to sample from Caucasian donor, presented as mean ± SEM. (B) Osmotic fragility curves for PIEZO1 E756del RBCs (n = 5) versus wild-type (n = 4) at ambient temperature. (C) Quantification of osmotic fragility tests showing mean relative tonicity at which there was 50% hemolysis ± SEM. ns, not significant. (D) Quantification of VAR2CSA expression on the surface of wild-type (n = 4) versus PIEZO1 E756del (n = 5) RBCs infected with P. falciparum strain NF54CSA, as measured by flow cytometry. Normalized MFI, mean fluorescence intensity relative to a control sample measured on the same day (*P = 0.045, nested ANOVA). n.s., not significant.

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