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

An inherited gain-of-function variant (E756del) in the mechanosensitive cationic channel PIEZO1 was 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. Yoda1 causes an increase in intracellular calcium associated with rapid echinocytosis that inhibits RBC invasion, without affecting parasite intraerythrocytic growth, division or egress. Notably, Yoda1 treatment significantly decreases merozoite attachment and subsequent RBC deformation. Intracellular Na+/K+ imbalance is unrelated to the mechanism of protection, although delayed RBC dehydration observed in the standard parasite culture medium RPMI/albumax further enhances the resistance to malaria conferred by Yoda1. The chemically unrelated Jedi2 PIEZO1 activator similarly causes echinocytosis and RBC dehydration associated with resistance to malaria invasion. Spiky outward membrane projections are anticipated to reduce the effective surface area required for both merozoite attachment and internalization upon pharmacological activation of PIEZO1. Globally, our findings indicate that the loss of the typical biconcave discoid shape of RBCs, together with an altered optimal surface to volume ratio, induced by PIEZO1 pharmacological activation prevent efficient P. falciparum invasion.

 

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In this study, the authors investigate the mechanism behind the protective effect of a gain-of-function variant in the PIEZO1 channel against severe malaria. They show that pharmacological activation of PIEZO1 using the compounds Yoda1 and Jedi2 can prevent Plasmodium falciparum infection of human red blood cells in vitro.

The authors find that Yoda1 treatment causes an increase in intracellular calcium and rapid echinocytosis, a process where the red blood cells develop spiky outward membrane projections. This results in a loss of the typical biconcave discoid shape of the red blood cells, which reduces the effective surface area required for both merozoite attachment and internalization, preventing efficient invasion by P. falciparum. Jedi2 similarly induces echinocytosis and RBC dehydration, leading to resistance to malaria invasion.

The authors note that intracellular Na+/K+ imbalance is unrelated to the mechanism of protection, although delayed RBC dehydration observed in the standard parasite culture medium further enhances the resistance to malaria conferred by Yoda1.

Overall, the findings suggest that the altered shape and surface area of red blood cells induced by pharmacological activation of PIEZO1 prevent efficient invasion by P. falciparum, and may provide a potential therapeutic target for malaria prevention.

Related Products

Cat.No. Product Name Information
S6678 Yoda1 Yoda1 acts as an agonist for both human and mouse Piezo1(EC50 of 17.1 and 26.6 μM for mouse and human). Yoda1 activates purified Piezo1 channels in the absence of other cellular components.

Related Targets

Mechanosensitive Channel