Pharmacological activation of PIEZO1 in human red blood cells prevents Plasmodium falciparum invasion

An inherited gain-of-function variant (E756 del) in the mechanosensitive cationic channel PIEZO1 was recently shown to confer a significant protection against severe malaria. Here, we demonstrate in vitro that human red blood cell (RBC) infection by Plasmodium falciparum is prevented by the pharmacological activation of PIEZO1. The PIEZO1 activator Yoda1 inhibits RBC invasion, without affecting parasite intraerythrocytic growth, division or egress. RBC dehydration, echinocytosis and intracellular Na+/K+ imbalance are unrelated to the mechanism of protection. Inhibition of invasion is maintained, even after a prolonged wash out of Yoda1. Similarly, the chemically unrelated activators Jedi1 and Jedi2 potently inhibit parasitemia, further indicating a PIEZO1-dependent mechanism. Notably, Yoda1 treatment significantly reduced RBC surface receptors of P. falciparum, and decreased merozoite attachment and subsequent RBC deformation. Altogether these data indicate that the pharmacological activation of Piezo1 in human RBCs inhibits malaria infection by impairing P. falciparum invasion.