The Central Role of cAMP in Regulating Plasmodium falciparum Merozoite Invasion of Human Erythrocytes

Michael J Blackman,Amrita Dawn,Niseema Pachikara,Gordon Langsley,Shailja Singh,Ghania Ramdani,Kunal R More,Chetan E Chitnis,Faiza Amber Siddiqui

doi:10.1371/journal.ppat.1004520

Abstract

All pathogenesis and death associated with Plasmodium falciparum malaria is due to parasite-infected erythrocytes. Invasion of erythrocytes by P. falciparum merozoites requires specific interactions between host receptors and parasite ligands that are localized in apical organelles called micronemes. Here, we identify cAMP as a key regulator that triggers the timely secretion of microneme proteins enabling receptor-engagement and invasion. We demonstrate that exposure of merozoites to a low K+ environment, typical of blood plasma, activates a bicarbonate-sensitive cytoplasmic adenylyl cyclase to raise cytosolic cAMP levels and activate protein kinase A, which regulates microneme secretion. We also show that cAMP regulates merozoite cytosolic Ca2+ levels via induction of an Epac pathway and demonstrate that increases in both cAMP and Ca2+ are essential to trigger microneme secretion. Our identification of the different elements in cAMP-dependent signaling pathways that regulate microneme secretion during invasion provides novel targets to inhibit blood stage parasite growth and prevent malaria.

Highlights

All the clinical symptoms of Plasmodium falciparum malaria are attributed to the blood stage of the parasite life cycle
We demonstrate that exposure of merozoites to a low K+ environment as found in blood plasma activates the bicarbonate-sensitive cytoplasmic adenylyl cyclase b (PfACb) leading to a rise in cytosolic cyclic adenosine monophosphate (cAMP) levels and activation of protein kinase A (PKA), which regulates microneme secretion
We show that exposure of merozoites to a low K+ environment, as found in blood plasma, leads to a rise in cytosolic cAMP levels due to activation of the cytoplasmic, bicarbonatesensitive adenylyl cyclase b (PfACb)

Summary

Introduction

All the clinical symptoms of Plasmodium falciparum malaria are attributed to the blood stage of the parasite life cycle. The intraerythrocytic stage of the life cycle is initiated when liberated P. falciparum merozoites invade and multiply within host red blood cells. Invasion of erythrocytes by P. falciparum merozoites is a complex multi-step process that is mediated by specific molecular interactions between red cell surface receptors and parasite protein ligands [1,2]. A number of parasite ligands that mediate receptor binding during invasion reside in apical membrane-bound organelles known as micronemes and rhoptries [1,2]. Secretion of these parasite ligands to the merozoite surface is critical for successful invasion [3,4]

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