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

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Abstract

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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Most cited references 44

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Gene Ontology: tool for the unification of biology

Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.

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Spiroindolones, a potent compound class for the treatment of malaria.

Matthias Rottmann, Case McNamara, Bryan K. S. Yeung … (2010)

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

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The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis.

Lucinda Rand, P. Rao, Sylvie Alonso … (2008)

The persistence of Mycobacterium tuberculosis despite prolonged chemotherapy represents a major obstacle for the control of tuberculosis. The mechanisms used by Mtb to persist in a quiescent state are largely unknown. Chemical genetic and genetic approaches were used here to study the physiology of hypoxic nonreplicating mycobacteria. We found that the intracellular concentration of ATP is five to six times lower in hypoxic nonreplicating Mtb cells compared with aerobic replicating bacteria, making them exquisitely sensitive to any further depletion. We show that de novo ATP synthesis is essential for the viability of hypoxic nonreplicating mycobacteria, requiring the cytoplasmic membrane to be fully energized. In addition, the anaerobic electron transport chain was demonstrated to be necessary for the generation of the protonmotive force. Surprisingly, the alternate ndh-2, but not -1, was shown to be the electron donor to the electron transport chain and to be essential to replenish the [NAD(+)] pool in hypoxic nonreplicating Mtb. Finally, we describe here the high bactericidal activity of the F(0)F(1) ATP synthase inhibitor R207910 on hypoxic nonreplicating bacteria, supporting the potential of this drug candidate for shortening the time of tuberculosis therapy.

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Author and article information

Contributors

Guglielmo Roma:

ORCID: http://orcid.org/0000-0002-8020-4219

Devendra Kumar Gupta

Sven Schuierer

Florian Nigsch

Walter Carbone:

ORCID: http://orcid.org/0000-0001-6150-8295

Anne-Marie Zeeman

Boon Heng Lee

Sam O Hofman

Bart W Faber

Judith Knehr

Erica Pasini

Bernd Kinzel

Pablo Bifani

Ghislain M C Bonamy

Tewis Bouwmeester

Clemens H M Kocken

Thierry Tidiane Diagana:

ORCID: http://orcid.org/0000-0002-8520-5683

Urszula Krzych: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 07 December 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e29605

Affiliations

[1 ]deptDepartment of Parasitology Biomedical Primate Research Centre RijswijkNetherlands

[2 ]Novartis Institutes for BioMedical Research BaselSwitzerland

[3 ]Novartis Institute for Tropical Diseases SingaporeSingapore

Walter Reed Army Institute of Research United States

Author notes

^#These authors contributed equally to this work.

[†]

These authors contributed equally to this work.

Author information

Annemarie Voorberg-van der Wel http://orcid.org/0000-0001-9403-0515

Guglielmo Roma http://orcid.org/0000-0002-8020-4219

Walter Carbone http://orcid.org/0000-0001-6150-8295

Thierry Tidiane Diagana http://orcid.org/0000-0002-8520-5683

Article

Publisher ID: 29605

DOI: 10.7554/eLife.29605

PMC ID: 5758109

PubMed ID: 29215331

SO-VID: c209af8e-75df-47c0-b16f-d07ee61e8361

License:

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

History

Date received : 15 June 2017

Date accepted : 05 December 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;

Award Recipient : Guglielmo Roma Clemens H M Kocken Thierry Tidiane Diagana

Funded by: FundRef http://dx.doi.org/10.13039/501100004167, Medicines for Malaria Venture;

Award Recipient : Clemens H M Kocken Thierry Tidiane Diagana

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award Recipient : Clemens H M Kocken

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award Recipient : Thierry Tidiane Diagana

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

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Author impact statement This comprehensive transcriptomic resource of dormant and replicating malaria liver parasites highlights the dearth of pathways that operate in the hypnozoites and the need to investigate druggability (i.e. selectivity and safety) of core pathways in malaria parasites.

ScienceOpen disciplines: Life sciences

Keywords: malaria,liver stages,hypnozoites,transcriptomics,plasmodium,plasmodium cynomolgi,other

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: malaria, liver stages, hypnozoites, transcriptomics, plasmodium, plasmodium cynomolgi, other

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

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Abstract

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Malaria vaccine development

Most cited references 44

Gene Ontology: tool for the unification of biology

Spiroindolones, a potent compound class for the treatment of malaria.

The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis.

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