Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility
Name
s41467-020-18624-0.pdf
Description
Published version
Size
2.04 MB
Format
Adobe PDF
Checksum (MD5)
e661ccc842b4d8495d4ae15ad9c687f7
Author(s)
Harding, Clare R
Sidik, Saima M
Petrova, Boryana
Gnädig, Nina F
Okombo, John
Herneisen, Alice L
Ward, Kurt E
Markus, Benedikt M
Boydston, Elizabeth A
Fidock, David A
Date Issued
2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
© 2020, The Author(s). 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-020-18624-0
