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

Clare R. Harding, Saima M. Sidik, Boryana Petrova, Nina F. Gnädig, John Okombo, Alice L. Herneisen, Kurt E. Ward, Benedikt M. Markus, Elizabeth A. Boydston, David A. Fidock and Sebastian Lourido ()
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Clare R. Harding: Whitehead Institute for Biomedical Research
Saima M. Sidik: Whitehead Institute for Biomedical Research
Boryana Petrova: Whitehead Institute for Biomedical Research
Nina F. Gnädig: Columbia University Irving Medical Center
John Okombo: Columbia University Irving Medical Center
Alice L. Herneisen: Whitehead Institute for Biomedical Research
Kurt E. Ward: Columbia University Irving Medical Center
Benedikt M. Markus: Whitehead Institute for Biomedical Research
Elizabeth A. Boydston: Whitehead Institute for Biomedical Research
David A. Fidock: Columbia University Irving Medical Center
Sebastian Lourido: Whitehead Institute for Biomedical Research

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18624-0

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