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

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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.

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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.
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.
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".

"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).

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.