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

Author

Listed:
  • Clare R. Harding

    (Whitehead Institute for Biomedical Research
    University of Glasgow)

  • 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
    University of Otago)

  • Benedikt M. Markus

    (Whitehead Institute for Biomedical Research
    University of Freiburg)

  • Elizabeth A. Boydston

    (Whitehead Institute for Biomedical Research)

  • David A. Fidock

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Sebastian Lourido

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

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.

Suggested Citation

  • 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 & Sebastian Lourid, 2020. "Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18624-0
    DOI: 10.1038/s41467-020-18624-0
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    Cited by:

    1. Xuefang Guo & Nuo Ji & Qinghong Guo & Mengting Wang & Huiyu Du & Jiajia Pan & Lihua Xiao & Nishith Gupta & Yaoyu Feng & Ningbo Xia, 2024. "Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Manjunatha Chandana & Aditya Anand & Sourav Ghosh & Rahul Das & Subhashree Beura & Sarita Jena & Amol Ratnakar Suryawanshi & Govindarajan Padmanaban & Viswanathan Arun Nagaraj, 2022. "Malaria parasite heme biosynthesis promotes and griseofulvin protects against cerebral malaria in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    3. Wenyan Wan & Hui Dong & De-Hua Lai & Jiong Yang & Kai He & Xiaoyan Tang & Qun Liu & Geoff Hide & Xing-Quan Zhu & L. David Sibley & Zhao-Rong Lun & Shaojun Long, 2023. "The Toxoplasma micropore mediates endocytosis for selective nutrient salvage from host cell compartments," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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