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. A gain-of-function mutation in the mechanically activated channel PIEZO1 is associated with resistance to the malaria parasite Plasmodium falciparum.
Original language | English (US) |
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Pages (from-to) | 443-455.e12 |
Journal | Cell |
Volume | 173 |
Issue number | 2 |
DOIs | |
State | Published - Apr 5 2018 |
Externally published | Yes |
Keywords
- PIEZO1
- cerebral malaria
- dehydration
- functional variants
- genomics
- human genetics
- ion channel
- malaria
- mechanotransduction
- red blood cell
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology