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

Autor: Faiza Amber Siddiqui, Chetan E. Chitnis, Gordon Langsley, Ghania Ramdani, Kunal R. More, Shailja Singh, Niseema Pachikara, Amrita Dawn
Přispěvatelé: International Centre for Genetic Engineering and Biotechnology [New Delhi] (ICGEB), Département Parasites et Insectes vecteurs - Department of Parasites and Insect Vectors, Institut Pasteur [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Program Support Grant from the Department of Biotechnology (DBT), Government of India.GL acknowledges INSERM, CNRS and Labex ParaFrap ANR-11-LABX-0024 for support. SS is a recipient of an Innovative Young Biotechnologist Award (IYBA) from DBT., European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009), European Project: 223044,EC:FP7:HEALTH,FP7-HEALTH-2007-B,MALSIG(2009), Institut Pasteur [Paris] (IP), Bos, Mireille, Towards the establishment of a permanent European Virtual Institute dedicated to Malaria Research (EVIMalaR). - EVIMALAR - - EC:FP7:HEALTH2009-10-01 - 2014-09-30 - 242095 - VALID, Signalling in life cycle stages of malaria parasites - MALSIG - - EC:FP7:HEALTH2009-02-01 - 2012-07-31 - 223044 - VALID
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: PLoS Pathogens
PLoS Pathogens, Public Library of Science, 2014, 10 (12), pp.e1004520. ⟨10.1371/journal.ppat.1004520⟩
PLoS Pathogens, Vol 10, Iss 12, p e1004520 (2014)
PLoS Pathogens, 2014, 10 (12), pp.e1004520. ⟨10.1371/journal.ppat.1004520⟩
ISSN: 1553-7366
1553-7374
Popis: 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.
Author Summary The blood stage of malaria parasites is responsible for all the morbidity and mortality associated with malaria. During the blood stage, malaria parasites invade and multiply within host erythrocytes. The process of erythrocyte invasion requires specific interactions between host receptors and parasite ligands. Many of the key parasite proteins that bind host receptors are localized in apical organelles called micronemes. Here, we demonstrate that cAMP serves as a key regulator that controls the timely secretion of microneme proteins during invasion. 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, bicarbonate-sensitive adenylyl cyclase β (PfACβ). A rise in cAMP activates protein kinase A (PKA), which regulates microneme secretion. In addition, cAMP triggers a rise in cytosolic Ca2+ levels through the Epac pathway. Increases in both cAMP and Ca2+ levels are essential for triggering microneme secretion. Identification of the different elements in the cAMP-dependent signaling pathways that regulate microneme secretion during invasion provides novel targets to block erythrocyte invasion, inhibit blood stage parasite growth and prevent malaria.
Databáze: OpenAIRE
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