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)

Abstract

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
• Status: Published
• Refereed: Yes
• 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 Research
• ISSN: 2041-1723
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
170084		Developing insights into Toxoplasma gondii pathogenesis through analysis of both parasite and host cell proteins required for the parasite's lifecycle	Clare Harding	Wellcome Trust (WELLCOTR)	103972/Z/14/Z	III - Bacteriology
304336		Iron usage in the eukaryotic parasite Toxoplasma gondii	Clare Harding	Wellcome Trust (WELLCOTR)	213455/Z/18/Z	III - Parasitology