1. Biochemistry
  2. Microbiology and Infectious Disease
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Deconvoluting heme biosynthesis to target blood-stage malaria parasites

  1. Paul A Sigala
  2. Jan R Crowley
  3. Jeffrey P Henderson
  4. Daniel E Goldberg Is a corresponding author
  1. Washington University School of Medicine, United States
Research Article
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Cite as: eLife 2015;4:e09143 doi: 10.7554/eLife.09143

Abstract

Heme metabolism is central to blood-stage infection by the malaria parasite, Plasmodium falciparum. Parasites retain a heme biosynthesis pathway but do not require its activity during infection of heme-rich erythrocytes, where they can scavenge host heme to meet metabolic needs. Nevertheless, heme biosynthesis in parasite-infected erythrocytes can be potently stimulated by exogenous 5-aminolevulinic acid (ALA), resulting in accumulation of the phototoxic intermediate, protoporphyrin IX (PPIX). Here we use photodynamic imaging, mass spectrometry, parasite gene disruption, and chemical probes to reveal that vestigial host enzymes in the cytoplasm of Plasmodium-infected erythrocytes contribute to ALA-stimulated heme biosynthesis and that ALA uptake depends on parasite-established permeability pathways. We show that PPIX accumulation in infected erythrocytes can be harnessed for antimalarial chemotherapy using luminol-based chemiluminescence and combinatorial stimulation by low-dose artemisinin to photoactivate PPIX to produce cytotoxic reactive oxygen. This photodynamic strategy has the advantage of exploiting host enzymes refractory to resistance-conferring mutations.

Article and author information

Author details

  1. Paul A Sigala

    1. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States
    Competing interests
    Paul A Sigala, Is a co-inventor on a provisional patent application entitled Combination Artemisinin and Chemiluminescent Photodynamic Therapy and Uses Therefor"".
  2. Jan R Crowley

    1. Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  3. Jeffrey P Henderson

    1. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  4. Daniel E Goldberg

    1. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States
    For correspondence
    1. goldberg@wusm.wustl.edu
    Competing interests
    Daniel E Goldberg, Is a co-inventor on a provisional patent application entitled Combination Artemisinin and Chemiluminescent Photodynamic Therapy and Uses Therefor"".

Reviewing Editor

  1. Jon Clardy, Reviewing Editor, Harvard Medical School, United States

Publication history

  1. Received: June 2, 2015
  2. Accepted: July 13, 2015
  3. Accepted Manuscript published: July 14, 2015 (version 1)
  4. Version of Record published: August 12, 2015 (version 2)

Copyright

© 2015, Sigala 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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