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A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans
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 chan...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183233/ https://www.ncbi.nlm.nih.gov/pubmed/32265284 http://dx.doi.org/10.1073/pnas.1919843117 |
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author | Nguetse, Christian N. Purington, Natasha Ebel, Emily R. Shakya, Bikash Tetard, Marilou Kremsner, Peter G. Velavan, Thirumalaisamy P. Egan, Elizabeth S. |
author_facet | Nguetse, Christian N. Purington, Natasha Ebel, Emily R. Shakya, Bikash Tetard, Marilou Kremsner, Peter G. Velavan, Thirumalaisamy P. Egan, Elizabeth S. |
author_sort | Nguetse, Christian N. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7183233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-71832332020-05-01 A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans Nguetse, Christian N. Purington, Natasha Ebel, Emily R. Shakya, Bikash Tetard, Marilou Kremsner, Peter G. Velavan, Thirumalaisamy P. Egan, Elizabeth S. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2020-04-21 2020-04-07 /pmc/articles/PMC7183233/ /pubmed/32265284 http://dx.doi.org/10.1073/pnas.1919843117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Nguetse, Christian N. Purington, Natasha Ebel, Emily R. Shakya, Bikash Tetard, Marilou Kremsner, Peter G. Velavan, Thirumalaisamy P. Egan, Elizabeth S. A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans |
title | A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans |
title_full | A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans |
title_fullStr | A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans |
title_full_unstemmed | A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans |
title_short | A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans |
title_sort | common polymorphism in the mechanosensitive ion channel piezo1 is associated with protection from severe malaria in humans |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183233/ https://www.ncbi.nlm.nih.gov/pubmed/32265284 http://dx.doi.org/10.1073/pnas.1919843117 |
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