1. Cell Biology
  2. Microbiology and Infectious Disease
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Plasmodium falciparum parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate

Research Article
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Cite this article as: eLife 2017;6:e23217 doi: 10.7554/eLife.23217

Abstract

Plasmodium falciparum parasites, the causative agents of malaria, modify their host erythrocyte to render them permeable to supplementary nutrient uptake from the plasma and for removal of toxic waste. Here we investigate the contribution of the rhoptry protein RhopH2, in the formation of new permeability pathways (NPPs) in Plasmodium-infected erythrocytes. We show RhopH2 interacts with RhopH1, RhopH3, the erythrocyte cytoskeleton and exported proteins involved in host cell remodeling. Knockdown of RhopH2 expression in cycle one leads to a depletion of essential vitamins and cofactors and decreased de novo synthesis of pyrimidines in cycle two. There is also a significant impact on parasite growth, replication and transition into cycle three. The uptake of solutes that use NPPs to enter erythrocytes is also reduced upon RhopH2 knockdown. These findings provide direct genetic support for the contribution of the RhopH complex in NPP activity and highlight the importance of NPPs to parasite survival.

Article and author information

Author details

  1. Natalie Counihan

    School of Medicine, Deakin University, Geelong, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8973-3344
  2. Scott A Chisholm

    School of Medicine, Deakin University, Geelong, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Hayley E Bullen

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Anubhav Srivastava

    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Paul R Sanders

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Thorey K Jonsdottir

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Greta E Weiss

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Sreejoyee Ghosh

    School of Medicine, Deakin University, Geelong, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Brendan S Crabb

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Darren J Creek

    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Paul R Gilson

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Tania F de Koning-Ward

    School of Medicine, Deakin University, Geelong, Australia
    For correspondence
    taniad@deakin.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5810-8063

Funding

National Health and Medical Research Council (1082157)

  • Paul R Gilson
  • Tania F de Koning-Ward

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

Ethics

Animal experimentation: Experiments involving the use of animals were performed in accordance with the recommendations of the Australian Government and the National Health and Medical Research Council Australian code of practice for the care and use of animals for scientific purposes. The protocols were approved by the Deakin University Animal Welfare Committee (approval number G37/2013).

Reviewing Editor

  1. Dominique Soldati-Favre, University of Geneva, Switzerland

Publication history

  1. Received: November 12, 2016
  2. Accepted: February 26, 2017
  3. Accepted Manuscript published: March 2, 2017 (version 1)
  4. Version of Record published: March 24, 2017 (version 2)

Copyright

© 2017, Counihan 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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Further reading

    1. Cell Biology
    2. Microbiology and Infectious Disease
    Daisuke Ito et al.
    Research Article Updated

    Malaria parasites evade immune detection by growth and replication within erythrocytes. After erythrocyte invasion, the intracellular pathogen must increase host cell uptake of nutrients from plasma. Here, we report that the parasite-encoded RhopH complex contributes to both invasion and channel-mediated nutrient uptake. As rhoph2 and rhoph3 gene knockouts were not viable in the human P. falciparum pathogen, we used conditional knockdowns to determine that the encoded proteins are essential and to identify their stage-specific functions. We exclude presumed roles for RhopH2 and CLAG3 in erythrocyte invasion but implicate a RhopH3 contribution either through ligand-receptor interactions or subsequent parasite internalization. These proteins then traffic via an export translocon to the host membrane, where they form a nutrient channel. Knockdown of either RhopH2 or RhopH3 disrupts the entire complex, interfering with organellar targeting and subsequent trafficking. Therapies targeting this complex should attack the pathogen at two critical points in its cycle.

    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease
    Edited by Prabhat Jha et al.
    Collection Updated

    eLife has published papers on many tropical diseases, including malaria, Ebola, leishmaniases, Dengue and African sleeping sickness.