Cell Reports
Volume 39, Issue 11, 14 June 2022, 110923
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Article
Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

https://doi.org/10.1016/j.celrep.2022.110923Get rights and content
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open access

Highlights

  • Human peroxiredoxin 6 (PRDX6) is internalized by P. falciparum blood stages

  • Inhibition of host PRDX6 causes lethal lipid-peroxidation damage in the parasite

  • Co-treatment with artemisinin and PRDX6 inhibitors overcomes artemisinin resistance

  • Targeting of a host enzyme like PRDX6 may prevent development of drug resistance

Summary

The uptake and digestion of host hemoglobin by malaria parasites during blood-stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid-peroxidation repair enzyme with phospholipase A2 (PLA2) activity. Inhibition of PRDX6 with a PLA2 inhibitor, Darapladib, increases lipid-peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance.

Keywords

Plasmodium falciparum
PRDX6
oxidative stress
lipid peroxidation
artemisinin
endocytosis
hemoglobin
host cell cytosol uptake
malaria
molecular parasitology

Research topic(s)

CP: Microbiology
CP: Metabolism

Data and code availability

  • The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the JPOSTrepo partner repository with the dataset identifier PXD029803.

  • Original western blot and fluorescent gel images, as well as raw flow cytometry data have been deposited at Mendeley and are publicly available as of the date of publication. The DOI is listed in the key resources table.

  • Microscopy data reported in this paper will be shared by the lead contact upon request.

  • This study did not generate new code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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