1. Microbiology and Infectious Disease

The Plasmodium Liver-Specific Protein 2 (LISP2) is an early marker of liver stage development

  1. Devendra Kumar Gupta
  2. Laurent Dembele
  3. Annemarie Voorberg-van der Wel
  4. Guglielmo Roma
  5. Andy Yip
  6. Vorada Chuenchob
  7. Niwat Kangwanrangsan
  8. Tomoko Ishino
  9. Ashley M Vaughan
  10. Stefan HI Kappe
  11. Erika L Flannery
  12. Jetsumon Sattabongkot
  13. Sebastian A Mikolajczak
  14. Pablo Bifani
  15. Clemens H M Kocken
  16. Thierry Tidiane Diagana  Is a corresponding author
  1. Novartis Institute for Tropical Diseases, United States
  2. Université des Sciences, des Techniques et des Technologies de Bamako, Mali
  3. Biomedical Primate Research Centre, Netherlands
  4. Novartis Institutes for BioMedical Research, Switzerland
  5. Novartis Institute for Tropical Diseases, Singapore
  6. Center for Infectious Disease Research, United States
  7. Mahidol University, Thailand
  8. Ehime University, Japan
https://doi.org/10.7554/eLife.43362
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Cite this article
  1. Devendra Kumar Gupta
  2. Laurent Dembele
  3. Annemarie Voorberg-van der Wel
  4. Guglielmo Roma
  5. Andy Yip
  6. Vorada Chuenchob
  7. Niwat Kangwanrangsan
  8. Tomoko Ishino
  9. Ashley M Vaughan
  10. Stefan HI Kappe
  11. Erika L Flannery
  12. Jetsumon Sattabongkot
  13. Sebastian A Mikolajczak
  14. Pablo Bifani
  15. Clemens H M Kocken
  16. Thierry Tidiane Diagana
(2019)
The Plasmodium Liver-Specific Protein 2 (LISP2) is an early marker of liver stage development
eLife 8:e43362.
https://doi.org/10.7554/eLife.43362
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Abstract

Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites, in vitro (P. cynomolgi) and in vivo (P. vivax), reveals that LISP2 expression discriminates between dormant hypnozoites and early developing parasites. We further demonstrate that prophylactic drugs selectively kill all LISP2 positive parasites, while LISP2 negative hypnozoites are only sensitive to anti-relapse drug tafenoquine. Our results provide novel biological insights in the initiation of liver stage schizogony and an early marker suitable for the development of drug discovery assays predictive of anti-relapse activity.

Data availability

All data generated during the study are submitted as supplementary source files.

The following previously published data sets were used

Article and author information

Author details

  1. Devendra Kumar Gupta

    Novartis Institute for Tropical Diseases, Emeryville, United States
    Competing interests
    Devendra Kumar Gupta, is employed by and/or shareholder of Novartis Pharma AG.

  2. Laurent Dembele

    Faculty of Pharmacy, Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Mali
    Competing interests
    No competing interests declared.

  3. Annemarie Voorberg-van der Wel

    Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9403-0515

  4. Guglielmo Roma

    Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Guglielmo Roma, is employed by and/or shareholder of Novartis Pharma AG.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8020-4219

  5. Andy Yip

    Novartis Institute for Tropical Diseases, Singapore, Singapore
    Competing interests
    Andy Yip, is employed by and/or shareholder of Novartis Pharma AG.

  6. Vorada Chuenchob

    Center for Infectious Disease Research, Seattle, United States
    Competing interests
    No competing interests declared.

  7. Niwat Kangwanrangsan

    Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.

  8. Tomoko Ishino

    Ehime University, Ehime, Japan
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2466-711X

  9. Ashley M Vaughan

    Center for Infectious Disease Research, Seattle, United States
    Competing interests
    No competing interests declared.

  10. Stefan HI Kappe

    Center for Infectious Disease Research, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1540-1731

  11. Erika L Flannery

    Center for Infectious Disease Research, Seattle, United States
    Competing interests
    Erika L Flannery, is employed by and/or shareholder of Novartis Pharma AG.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0665-7954

  12. Jetsumon Sattabongkot

    Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3938-4588

  13. Sebastian A Mikolajczak

    Novartis Institute for Tropical Diseases, Emeryville, United States
    Competing interests
    Sebastian A Mikolajczak, is employed by and/or shareholder of Novartis Pharma AG.

  14. Pablo Bifani

    Novartis Institute for Tropical Diseases, Singapore, Singapore
    Competing interests
    Pablo Bifani, is employed by and/or shareholder of Novartis Pharma AG.

  15. Clemens H M Kocken

    Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
    Competing interests
    No competing interests declared.

  16. Thierry Tidiane Diagana

    Novartis Institute for Tropical Diseases, Emeryville, United States
    For correspondence
    thierry.diagana@novartis.com
    Competing interests
    Thierry Tidiane Diagana, is employed by and/or shareholder of Novartis Pharma AG..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8520-5683

Funding

Bill and Melinda Gates Foundation (OPP1141292)

  • Guglielmo Roma
  • Clemens H M Kocken
  • Thierry Tidiane Diagana

Bill and Melinda Gates Foundation (OPP1137694)

  • Sebastian A Mikolajczak

Funders have no role in the design of the study.

Ethics

Animal experimentation: Ethics statement included in the method section of the manuscript.

Copyright

© 2019, Gupta et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Devendra Kumar Gupta
  2. Laurent Dembele
  3. Annemarie Voorberg-van der Wel
  4. Guglielmo Roma
  5. Andy Yip
  6. Vorada Chuenchob
  7. Niwat Kangwanrangsan
  8. Tomoko Ishino
  9. Ashley M Vaughan
  10. Stefan HI Kappe
  11. Erika L Flannery
  12. Jetsumon Sattabongkot
  13. Sebastian A Mikolajczak
  14. Pablo Bifani
  15. Clemens H M Kocken
  16. Thierry Tidiane Diagana
(2019)
The Plasmodium Liver-Specific Protein 2 (LISP2) is an early marker of liver stage development
eLife 8:e43362.
https://doi.org/10.7554/eLife.43362

Share this article

https://doi.org/10.7554/eLife.43362

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Further reading

    1. Microbiology and Infectious Disease

    A comparative transcriptomic analysis of replicating and dormant liver stages of the relapsing malaria parasite Plasmodium cynomolgi

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    Plasmodium liver hypnozoites, which cause disease relapse, are widely considered to be the last barrier towards malaria eradication. The biology of this quiescent form of the parasite is poorly understood which hinders drug discovery. We report a comparative transcriptomic dataset of replicating liver schizonts and dormant hypnozoites of the relapsing parasite Plasmodium cynomolgi. Hypnozoites express only 34% of Plasmodium physiological pathways, while 91% are expressed in replicating schizonts. Few known malaria drug targets are expressed in quiescent parasites, but pathways involved in microbial dormancy, maintenance of genome integrity and ATP homeostasis were robustly expressed. Several transcripts encoding heavy metal transporters were expressed in hypnozoites and the copper chelator neocuproine was cidal to all liver stage parasites. This transcriptomic dataset is a valuable resource for the discovery of vaccines and effective treatments to combat vivax malaria.

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