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Cell. 2018 Apr 5;173(2):443-455.e12. doi: 10.1016/j.cell.2018.02.047. Epub 2018 Mar 22.

Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection.

Author information

1
Howard Hughes Medical Institute, Department of Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California, San Diego, San Diego, CA, USA.
3
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
4
Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
5
DIMNP, CNRS, INSERM, University Montpellier, Montpellier, France.
6
Leiden Malaria Research Group, Department of Parasitology, Leiden University Medical Center (LUMC), 2333ZA Leiden, the Netherlands.
7
Genomics Institute of the Novartis Research Foundation, La Jolla, CA, USA.
8
Université Côte d'Azur, Centre National de la Recherche Scientifique, Paris, France; Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST, Valbonne, France.
9
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA; Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
10
Howard Hughes Medical Institute, Department of Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: ardem@scripps.edu.

Abstract

Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.

KEYWORDS:

PIEZO1; cerebral malaria; dehydration; functional variants; genomics; human genetics; ion channel; malaria; mechanotransduction; red blood cell

PMID:
29576450
PMCID:
PMC5889333
[Available on 2019-04-05]
DOI:
10.1016/j.cell.2018.02.047

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