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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / physiology
  • Cells, Cultured
  • Cyclic AMP / physiology*
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Erythrocytes / drug effects
  • Erythrocytes / parasitology*
  • Erythrocytes / pathology
  • Humans
  • Hydrogen-Ion Concentration
  • Malaria, Falciparum / physiopathology*
  • Merozoites / growth & development*
  • Merozoites / physiology
  • Plasmodium falciparum / pathogenicity*
  • Potassium / pharmacology
  • Signal Transduction / physiology

Substances

  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Potassium
  • Calcium

Grant support

The research leading to these results has received funding through a Program Support Grant from the Department of Biotechnology (DBT), Government of India and the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreements No 242095 (EVIMALAR) & 223044 (MALSIG). 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.