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

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...

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Bibliographic Details
Published in:PLoS pathogens 2014-12, Vol.10 (12), p.e1004520-e1004520
Main Authors: Dawn, Amrita, Singh, Shailja, More, Kunal R, Siddiqui, Faiza Amber, Pachikara, Niseema, Ramdani, Ghania, Langsley, Gordon, Chitnis, Chetan E
Format: Article
Language:English
Subjects:
Antigens
Biochemistry, Molecular Biology
Biology and Life Sciences
Calcium - physiology
Cell research
Cells, Cultured
Cyclic adenylic acid
Cyclic AMP - physiology
Cyclic AMP-Dependent Protein Kinases - physiology
Erythrocytes
Erythrocytes - drug effects
Erythrocytes - parasitology
Erythrocytes - pathology
Genomics
Health aspects
Host-parasite relationships
Humans
Hydrogen-Ion Concentration
Kinases
Life Sciences
Malaria
Malaria, Falciparum - physiopathology
Merozoites - growth & development
Merozoites - physiology
Microbiological research
Parasites
Plasmodium falciparum
Plasmodium falciparum - pathogenicity
Potassium - pharmacology
Signal Transduction - physiology
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1004520