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PLoS Pathog. 2014 Dec 18;10(12):e1004520. doi: 10.1371/journal.ppat.1004520. eCollection 2014 Dec.

The central role of cAMP in regulating Plasmodium falciparum merozoite invasion of human erythrocytes.

Author information

1
Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
2
Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India; Malaria Parasite Biology and Vaccines Unit, Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France.
3
Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France.

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.

PMID:
25522250
PMCID:
PMC4270784
DOI:
10.1371/journal.ppat.1004520
[Indexed for MEDLINE]
Free PMC Article

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