An essential dual-function complex mediates erythrocyte invasion and channel-mediated nutrient uptake in malaria parasites

  1. Daisuke Ito
  2. Marc A Schureck
  3. Sanjay A Desai  Is a corresponding author
  1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States

Abstract

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.

Article and author information

Author details

  1. Daisuke Ito

    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States
    Competing interests
    No competing interests declared.
  2. Marc A Schureck

    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States
    Competing interests
    No competing interests declared.
  3. Sanjay A Desai

    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States
    For correspondence
    sdesai@niaid.nih.gov
    Competing interests
    Sanjay A Desai, Is a named inventor on US and international patent applications and an issued US patent on the drug targets presented in this manuscript (Inhibitors of the plasmodial surface anion channel as antimalarials".
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2150-2483

Funding

Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Intramural Research Support)

  • Daisuke Ito
  • Marc A Schureck
  • Sanjay A Desai

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

Ethics

Animal experimentation: Polyclonal antibody production in rabbits was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health by SDIX, a facility accredited by OLAW (Assurance #: A3975-01) and AAALAC (Delaware Accreditation # 00806).

Reviewing Editor

  1. Jon Clardy, Harvard Medical School, United States

Publication history

  1. Received: November 19, 2016
  2. Accepted: February 16, 2017
  3. Accepted Manuscript published: February 21, 2017 (version 1)
  4. Version of Record published: March 14, 2017 (version 2)

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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  1. Daisuke Ito
  2. Marc A Schureck
  3. Sanjay A Desai
(2017)
An essential dual-function complex mediates erythrocyte invasion and channel-mediated nutrient uptake in malaria parasites
eLife 6:e23485.
https://doi.org/10.7554/eLife.23485
  1. Further reading

Further reading

    1. Microbiology and Infectious Disease
    2. Cell Biology
    Emma S Sherling, Ellen Knuepfer ... Christiaan van Ooij
    Research Article Updated

    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.

    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.