• Open Access

Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes

Authors

  • Audrey Sicard,

    1. INSERM U609/Inserm-EPFL Joint Laboratory, Global Health Institute
    2. Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
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    • A. Sicard and J.-P. Semblat contributed equally to this work.

  • Jean-Philippe Semblat,

    1. INSERM U609/Inserm-EPFL Joint Laboratory, Global Health Institute
    2. Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
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    • A. Sicard and J.-P. Semblat contributed equally to this work.

  • Caroline Doerig,

    1. INSERM U609/Inserm-EPFL Joint Laboratory, Global Health Institute
    2. Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
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  • Romain Hamelin,

    1. Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
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  • Marc Moniatte,

    1. Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
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  • Dominique Dorin-Semblat,

    1. INSERM U609/Inserm-EPFL Joint Laboratory, Global Health Institute
    2. Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
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  • Julie A. Spicer,

    1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
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  • Anubhav Srivastava,

    1. Division of Infection and Immunity, Faculty of Biomedical Life Sciences, & Wellcome Trust Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, Scotland, UK.
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  • Silke Retzlaff,

    1. Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany.
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  • Volker Heussler,

    1. Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany.
    2. Institute of Cell Biology, University of Bern, Baltzerstasse 4, 3012 Bern, Switzerland.
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  • Andrew P. Waters,

    1. Division of Infection and Immunity, Faculty of Biomedical Life Sciences, & Wellcome Trust Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, Scotland, UK.
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  • Christian Doerig

    Corresponding author
    1. INSERM U609/Inserm-EPFL Joint Laboratory, Global Health Institute
    2. Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
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E-mail christian.doerig@epfl.ch; Tel. (+41) 21 693 0983; Fax (+41) 21 693 7220.

Summary

Merozoites of malaria parasites invade red blood cells (RBCs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. Here, we report that a protein kinase-mediated signalling pathway involving host RBC PAK1 and MEK1, which do not have orthologues in the Plasmodium kinome, is selectively stimulated in Plasmodium falciparum-infected (versus uninfected) RBCs, as determined by the use of phospho-specific antibodies directed against the activated forms of these enzymes. Pharmacological interference with host MEK and PAK function using highly specific allosteric inhibitors in their known cellular IC50 ranges results in parasite death. Furthermore, MEK inhibitors have parasiticidal effects in vitro on hepatocyte and erythrocyte stages of the rodent malaria parasite Plasmodium berghei, indicating conservation of this subversive strategy in malaria parasites. These findings have profound implications for the development of novel strategies for antimalarial chemotherapy.

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