Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility

Harding, C. R. (2020) Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility. Nature Communications, 11, 4813. (doi: 10.1038/s41467-020-18624-0) (PMID:32968076) (PMCID:PMC7511413)

[img] Text
222680.pdf - Published Version
Available under License Creative Commons Attribution.



Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deleting the homologous gene in P. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Harding, Dr Clare
Authors: Harding, C. R.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Nature Communications 11:4813
Publisher Policy:Reproduced under a Creative Commons licence

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170084Developing insights into Toxoplasma gondii pathogenesis through analysis of both parasite and host cell proteins required for the parasite's lifecycleClare HardingWellcome Trust (WELLCOTR)103972/Z/14/ZIII - Bacteriology
304336Iron usage in the eukaryotic parasite Toxoplasma gondiiClare HardingWellcome Trust (WELLCOTR)213455/Z/18/ZIII - Parasitology