Host Genetic Predisposition to Malaria

Nguetse, Christian N.; Egan, Elizabeth S.

doi:10.1007/978-1-4614-8757-9_139-1

Cited by 2 publications

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“…Together with the previous mechanistic work on mouse PIEZO1 GOF mutations and P. berghei ANKA, these data firmly establish PIEZO1 as an important host susceptibility factor for malaria. Though the list of innate susceptibility determinants for severe malaria includes a range of factors such as hemoglobin variants, enzymes, membrane proteins, and immune-related molecules (7,42), PIEZO1 is unique because it is considered a druggable molecule (43). The discovery that the E756del allele is associated with protection from severe malaria in patients suggests that PIEZO1 has potential as a compelling target for a host-directed therapy for malaria.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of studies have shown that one of the strongest protective factors is heterozygosity for the hemoglobin S allele (HbAS), which leads to impaired parasite proliferation at low oxygen tension and defects in the trafficking system for parasite-encoded exported proteins (2)(3)(4)(5)(6). Many other candidate susceptibility loci reside in genes encoding membrane or structural proteins of the red blood cell (7). However, associations between established candidate loci and malaria severity explain only a fraction of the variance in clinical outcome, suggesting additional susceptibility factors have yet to be discovered (8).…”

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confidence: 99%

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

Nguetse

Purington

Ebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Nguetse

Purington

Ebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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

Nguetse

Purington

Shakya

et al. 2019

Preprint

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Running title: PIEZO1 polymorphism and severe malaria in African children Abstract 1Malaria caused by the Apicomplexan parasite Plasmodium falciparum has served as a strong 2 evolutionary force throughout human history, selecting for red blood cell polymorphisms that 3 confer innate protection against severe disease. Recently, gain-of-function mutations in the 4 mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, 5 blood-brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-6 of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the 7 possibility that it is under positive selection due to malaria. Here we used a case-control study 8 design to test for an association between PIEZO1 E756del and malaria severity among children 9in Gabon. We found that the E756del variant is strongly associated with protection against severe 10 malaria in heterozygotes, independent of the protection conferred by the sickle cell trait 11 (hemoglobin AS). In vitro experiments using donor red blood cells failed to find an effect of 12E756del on parasite growth, suggesting this variant confers a mild channel defect and/or that its 13 protective effect may be mediated by other tissue types in vivo. Nonetheless, we show that Yoda1, 14 a small molecule agonist of PIEZO1, has potent antimalarial activity in both E756del and wild-15 type red blood cells. Our findings demonstrate that PIEZO1 is an important innate determinant of 16 malaria susceptibility in humans and holds potential as druggable host target for malaria control. 17 18

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Host Genetic Predisposition to Malaria

Cited by 2 publications

References 255 publications

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

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

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

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