Journal
CELL
Volume 173, Issue 2, Pages 443-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.02.047
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Funding
- NIH [R01 DE022358, AI090141, AI103058]
- Calibr-GHDDI Gates postdoctoral fellowship
- A.P. Giannini postdoctoral fellowship
- NIH NCATS CTSA [UL1TR001114]
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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 Plasmodiuminfection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.
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