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Nat Med. 2014 Mar;20(3):307-12. doi: 10.1038/nm.3461. Epub 2014 Feb 9.

Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures.

Author information

1
1] Sorbonne Universités, Université Pierre et Marie Curie Paris 6, UMR S945, Paris, France. [2] Institut National de la Santé et de la Recherche Médicale, U945, Paris, France. [3].
2
1] Sorbonne Universités, Université Pierre et Marie Curie Paris 6, UMR S945, Paris, France. [2] Institut National de la Santé et de la Recherche Médicale, U945, Paris, France.
3
Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
4
1] Division of Immuno-Virology, Institute of Emerging Diseases and Innovative Therapies, Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay-aux-Roses, France. [2] Université Paris-Sud XI, UMRE01, Orsay, France.
5
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
6
Service de Chirurgie Digestive, Hépato-Bilio-Pancréatique et Transplantation Hépatique, Hôpital Pitié-Salpêtrière, Paris, France.
7
Department of Chemistry, Imperial College London, South Kensington Campus, London, UK.
8
Novartis Institute for Tropical Diseases, Singapore.
9
1] Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France. [2] Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France.
10
1] Sorbonne Universités, Université Pierre et Marie Curie Paris 6, UMR S945, Paris, France. [2] Institut National de la Santé et de la Recherche Médicale, U945, Paris, France. [3] Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service Parasitologie-Mycologie, Paris, France.

Abstract

Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compounds that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, experimentally infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept experiment, we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biology and the search for compounds that kill hypnozoites or disrupt their quiescence.

PMID:
24509527
DOI:
10.1038/nm.3461
[Indexed for MEDLINE]

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