1. Microbiology and Infectious Disease

Transcriptomic analysis reveals reduced transcriptional activity in the malaria parasite Plasmodium cynomolgi during progression into dormancy

  1. Nicole L Bertschi
  2. Annemarie Voorberg-van der Wel
  3. Anne-Marie Zeeman
  4. Sven Schuierer
  5. Florian Nigsch
  6. Walter Carbone
  7. Judith Knehr
  8. Devendra Kumar Gupta
  9. Sam O Hofman
  10. Nicole van der Werff
  11. Ivonne Nieuwenhuis
  12. Els Klooster
  13. Bart W Faber
  14. Erika L Flannery
  15. Sebastian Mikolajczak
  16. Binesh Shrestha
  17. Martin Beibel
  18. Tewis Bouwmeester
  19. Niwat Kangwanrangsan
  20. Jetsumon Sattabongkot
  21. Thierry Tidiane Diagana
  22. Clemens H M Kocken  Is a corresponding author
  23. Guglielmo Roma  Is a corresponding author
  1. Novartis Institutes for BioMedical Research, Switzerland
  2. Biomedical Primate Research Centre, Netherlands
  3. Novartis Institute for Tropical Diseases, United States
  4. Mahidol University, Thailand
https://doi.org/10.7554/eLife.41081
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  1. Nicole L Bertschi
  2. Annemarie Voorberg-van der Wel
  3. Anne-Marie Zeeman
  4. Sven Schuierer
  5. Florian Nigsch
  6. Walter Carbone
  7. Judith Knehr
  8. Devendra Kumar Gupta
  9. Sam O Hofman
  10. Nicole van der Werff
  11. Ivonne Nieuwenhuis
  12. Els Klooster
  13. Bart W Faber
  14. Erika L Flannery
  15. Sebastian Mikolajczak
  16. Binesh Shrestha
  17. Martin Beibel
  18. Tewis Bouwmeester
  19. Niwat Kangwanrangsan
  20. Jetsumon Sattabongkot
  21. Thierry Tidiane Diagana
  22. Clemens H M Kocken
  23. Guglielmo Roma
(2018)
Transcriptomic analysis reveals reduced transcriptional activity in the malaria parasite Plasmodium cynomolgi during progression into dormancy
eLife 7:e41081.
https://doi.org/10.7554/eLife.41081
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Abstract

Relapses of Plasmodium dormant liver hypnozoites compromise malaria eradication efforts. New radical cure drugs are urgently needed, yet the vast gap in knowledge of hypnozoite biology impedes drug discovery. We previously unraveled the transcriptome of 6 to 7 day-old P. cynomolgi liver stages, highlighting pathways associated with hypnozoite dormancy (Voorberg-van der Wel, 2017). We now extend these findings by transcriptome profiling of 9 to 10 day-old liver stage parasites, thus revealing for the first time the maturation of the dormant stage over time. Although progression of dormancy leads to a 10-fold decrease in transcription and expression of only 840 genes, including genes associated with housekeeping functions, we show that pathways involved in quiescence, energy metabolism and maintenance of genome integrity remain the prevalent pathways active in mature hypnozoites.

Data availability

The raw RNA-sequencing reads are available in the NCBI Short Read Archive (https://www.ncbi.nlm.nih.gov/sra) under accession number SRP096160.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Nicole L Bertschi

    Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Nicole L Bertschi, employed by and/or shareholders of Novartis Pharma AG.

  2. 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

  3. Anne-Marie Zeeman

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

  4. Sven Schuierer

    Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Sven Schuierer, employed by and/or shareholders of Novartis Pharma AG.

  5. Florian Nigsch

    Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Florian Nigsch, employed by and/or shareholders of Novartis Pharma AG.

  6. Walter Carbone

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Walter Carbone, employed by and/or shareholders of Novartis Pharma AG.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6150-8295

  7. Judith Knehr

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Judith Knehr, employed by and/or shareholders of Novartis Pharma AG.

  8. Devendra Kumar Gupta

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

  9. Sam O Hofman

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

  10. Nicole van der Werff

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

  11. Ivonne Nieuwenhuis

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

  12. Els Klooster

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

  13. Bart W Faber

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

  14. Erika L Flannery

    Novartis Institute for Tropical Diseases, Emeryville, United States
    Competing interests
    Erika L Flannery, employed by and/or shareholders of Novartis Pharma AG.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0665-7954

  15. Sebastian Mikolajczak

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

  16. Binesh Shrestha

    Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Binesh Shrestha, employed by and/or shareholders of Novartis Pharma AG.

  17. Martin Beibel

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Martin Beibel, employed by and/or shareholders of Novartis Pharma AG.

  18. Tewis Bouwmeester

    Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Tewis Bouwmeester, employed by and/or shareholders of Novartis Pharma AG.

  19. Niwat Kangwanrangsan

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

  20. 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

  21. Thierry Tidiane Diagana

    Novartis Institute for Tropical Diseases, Emeryville, United States
    Competing interests
    Thierry Tidiane Diagana, employed by and/or shareholders of Novartis Pharma AG.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8520-5683

  22. Clemens H M Kocken

    Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
    For correspondence
    kocken@bprc.nl
    Competing interests
    No competing interests declared.

  23. Guglielmo Roma

    Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    For correspondence
    guglielmo.roma@novartis.com
    Competing interests
    Guglielmo Roma, employed by and shareholders of Novartis Pharma AG.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8020-4219

Funding

Bill and Melinda Gates Foundation

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

Wellcome

  • Thierry Tidiane Diagana
  • Clemens H M Kocken

Medicines for Malaria Venture

  • Thierry Tidiane Diagana
  • Clemens H M Kocken

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Nonhuman primates were used because no other models (in vitro or in vivo) were suitable for the aims of this project. The research protocol was approved by the local independent ethical committee conform Dutch law (BPRC Dier Experimenten Commissie, DEC, agreement number #708). Details are described by Voorberg-van der Wel [4].

Copyright

© 2018, Bertschi 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. Nicole L Bertschi
  2. Annemarie Voorberg-van der Wel
  3. Anne-Marie Zeeman
  4. Sven Schuierer
  5. Florian Nigsch
  6. Walter Carbone
  7. Judith Knehr
  8. Devendra Kumar Gupta
  9. Sam O Hofman
  10. Nicole van der Werff
  11. Ivonne Nieuwenhuis
  12. Els Klooster
  13. Bart W Faber
  14. Erika L Flannery
  15. Sebastian Mikolajczak
  16. Binesh Shrestha
  17. Martin Beibel
  18. Tewis Bouwmeester
  19. Niwat Kangwanrangsan
  20. Jetsumon Sattabongkot
  21. Thierry Tidiane Diagana
  22. Clemens H M Kocken
  23. Guglielmo Roma
(2018)
Transcriptomic analysis reveals reduced transcriptional activity in the malaria parasite Plasmodium cynomolgi during progression into dormancy
eLife 7:e41081.
https://doi.org/10.7554/eLife.41081

Share this article

https://doi.org/10.7554/eLife.41081

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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

    Annemarie Voorberg-van der Wel, Guglielmo Roma ... Thierry Tidiane Diagana
    Tools and Resources Updated

    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.