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

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.

Structural and evolutionary divergence of cyclic nucleotide binding domains in eukaryotic pathogens: Implications for drug design

“…6), which are known to play important roles in pathogenesis [6, 30]. P. falciparum , the species responsible for the majority of malariarelated deaths, has three CNB-containing proteins, namely PfPKA-R, PfPKG and Rap guanine nucleotide exchange factor (PfEpac) [15]. P. vivax, P. berghei, P. yoelii, P. knowlesi, P. reichenowi, and P. chabaudi also encode multiple CNB domains in their genomes.…”

“…Even if the role of S610 phosphorylation in invasion has not been clearly demonstrated, PKA-mediated phosphorylation of a wide range of parasite proteins takes place prior to merozoite egress [14]. Merozoite egress and reinvasion of new red blood cells depend on cAMP-dependent PKA [15] and merozoite egress can also be regulated by cGMP-PKG [9,16]. Clearly, both cAMP and cGMP are critical secondary messengers in malaria parasite biology.…”

Signaling transcript profile of the asexual intraerythrocytic development cycle of Plasmodium falciparum induced by melatonin and cAMP

“…Recently, cAMP has been identified as a key regulator that triggers the timely secretion of microneme proteins, enabling receptor engagement and invasion [22]. This study also observed that cAMP increases merozoite cytosolic Ca2+ levels via induction of the Epac pathway; together, they are involved in the invasion process [22].…”

“…This study also observed that cAMP increases merozoite cytosolic Ca2+ levels via induction of the Epac pathway; together, they are involved in the invasion process [22]. Moreover, our group reported that the cAMP analog adenosine 3′,5′-cyclic monophosphate N6-benzoyl/PKA activator (6-Bz-cAMP) is able to increase the schizont (S) stage, leading to progression of the asexual stage of the life cycle and modulation of PFNF-YB transcription factor expression during the intraerythrocytic cycle in P. falciparum [23].…”

Protein Kinase A Negatively Regulates Ca2+ signaling in Toxoplasma gondii

“…http://dx.doi.org/10.1101/265371 doi: bioRxiv preprint first posted online Feb. 14, 2018; the cytoplasmic tail of the parasite adhesin AMA1 22,23 and may be linked to Ca 2+ signalling 13 .…”