Deconvoluting heme biosynthesis to target blood-stage malaria parasites

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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.

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Paul A Sigala

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"".
Jan R Crowley

Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, United States

Competing interests
No competing interests declared.
Jeffrey P Henderson

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States

Competing interests
No competing interests declared.
Daniel E Goldberg

Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States

For correspondence
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"".

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