Red blood cell signaling is functionally conserved in Plasmodium invasion

It is widely recognized that <i>Plasmodium</i> merozoites secrete ligands that interact with RBC receptors. Meanwhile the question on whether these interactions trigger RBC signals essential for invasion remains unresolved. There is evidence that <i>Plasmodium falciparum</i> parasites manipulate native RBC Ca²⁺ signaling to facilitate invasion. Here, we demonstrate a key role of RBC Ca²⁺ influx that is conserved across different <i>Plasmodium</i> species during invasion. RH5-basigin interaction triggers RBC cAMP increase to promote Ca²⁺ influx. The RBC signaling pathways can be blocked by a range of inhibitors during <i>Plasmodium</i> invasion, providing the evidence of a functionally conserved host cAMP-Ca²⁺ signaling that drives invasion and junction formation. Furthermore, RH5-basigin binding induces a pre-existing multimeric RBC membrane complex to undergo increased protein association containing the cAMP-inducing β-adrenergic receptor. Our work presents evidence of a conserved host cell signaling cascade necessary for <i>Plasmodium</i> invasion and will create opportunities to therapeutically target merozoite invasion.