1. Microbiology and Infectious Disease
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The Plasmodium falciparum rhoptry protein RhopH3 plays essential roles in host cell invasion and nutrient uptake

  1. Emma S Sherling
  2. Ellen Knuepfer
  3. Joseph A Brzostowski
  4. Louis H Miller
  5. Michael J Blackman  Is a corresponding author
  6. Christiaan van Ooij  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. National Institute of Allergy and Infectious Disease, National Institute of Health, United States
  3. London School of Hygiene and Tropical Medicine, United Kingdom
Research Article
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Cite this article as: eLife 2017;6:e23239 doi: 10.7554/eLife.23239

Abstract

Merozoites of the protozoan parasite responsible for the most virulent form of malaria, Plasmodium falciparum, invade erythrocytes. Invasion involves discharge of rhoptries, specialized secretory organelles. Once intracellular, parasites induce increased nutrient uptake by generating new permeability pathways (NPP) including a Plasmodium surface anion channel (PSAC). RhopH1/Clag3, one member of the three-protein RhopH complex, is important for PSAC/NPP activity. However, the roles of the other members of the RhopH complex in PSAC/NPP establishment are unknown and it is unclear whether any of the RhopH proteins play a role in invasion. Here we demonstrate that RhopH3, the smallest component of the complex, is essential for parasite survival. Conditional truncation of RhopH3 substantially reduces invasive capacity. Those mutant parasites that do invade are defective in nutrient import and die. Our results identify a dual role for RhopH3 that links erythrocyte invasion to formation of the PSAC/NPP essential for parasite survival within host erythrocytes.

Article and author information

Author details

  1. Emma S Sherling

    1. The Francis Crick Institute, London, United Kingdom
    2. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institute of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ellen Knuepfer

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Joseph A Brzostowski

    Laboratory of Immunogenetics Imaging Facility, National Institute of Allergy and Infectious Disease, National Institute of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Louis H Miller

    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institute of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael J Blackman

    1. The Francis Crick Institute, London, United Kingdom
    2. Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
    For correspondence
    Mike.Blackman@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  6. Christiaan van Ooij

    The Francis Crick Institute, London, United Kingdom
    For correspondence
    Christiaan.vanOoij@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6099-6183

Funding

Wellcome (FC001043)

  • Michael J Blackman

Cancer Research UK (FC001043)

  • Michael J Blackman

National Institutes of Health

  • Louis H Miller

Medical Research Council (FC001043)

  • Michael J Blackman

Wellcome (095836/Z/11/Z)

  • Christiaan van Ooij

Wellcome (013459/Z/14/Z)

  • Emma S Sherling

National Institutes of Health

  • Emma S Sherling

National Institutes of Health

  • Joseph A Brzostowski

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

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. Accepted Manuscript updated: March 3, 2017 (version 2)
  5. Version of Record published: March 24, 2017 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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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
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    Collection Updated

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