Red blood cell signaling is functionally conserved in Plasmodium invasion

It is widely recognized that Plasmodium 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 Plasmodium falciparum parasites manipulate native RBC Ca²⁺ signaling to facilitate invasion. Here, we demonstrate a key role of RBC Ca²⁺ influx that is conserved across different Plasmodium 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 Plasmodium 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 Plasmodium invasion and will create opportunities to therapeutically target merozoite invasion.