PIEZO1-dependent erythrocyte dehydration as the mechanism for selection of an allele protecting from severe malaria

Abstract PIEZO1 is a cation specific mechanoreceptor channel implicated in red blood cell (RBC) volume homeostasis. Several PIEZO1 gain of function (GoF) variants demonstrate delayed channel inactivation and can cause hereditary xerocytosis (HX), a disease characterized by hemolytic anemia, RBC dehydration, and shape distortion. The milder PIEZO1 E756del GoF variant, prevalent in populations of African descent, protects carriers from severe malaria caused by Plasmodium falciparum and ameliorate disease in a rodent malaria model. To explore the mechanism of this malaria protection, P. falciparum infection of human PIEZO1 E756del RBC was analyzed in shear-stressed and static cultures with and without Yoda1, a PIEZO1 agonist. RBC dehydration was a common pathophysiological factor affecting parasite replication in both culture conditions. PIEZO1 channel opening by either Yoda1 or shear stress produced dehydration-dependent cell hemolysis, inhibiting P. falciparum infection. Since the physiological activator of PIEZO1 in circulating RBC is shear stress, we propose that shear stress-induced dehydration, disproportionally affecting RBC of GoF PIEZO1 E756del carriers, makes erythrocytes less habitable for P. falciparum to the point of hemolysis, and thus ameliorates malaria in GoF PIEZO1 E756del carriers. More generally, RBC dehydration processes may be a pathway for protection from the severe form of malaria common to several hematological disorders, including sickle cell trait. Key points PIEZO1 E756del activation in African American donor RBC provokes dehydration-dependent cell hemolysis, impairing P. falciparum replication. RBC dehydration could be a malaria ameliorating factor in several known RBC hematological disorders, including sickle cell trait.