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The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

Author

Listed:
  • Min Zhang

    (University of South Florida)

  • Chengqi Wang

    (University of South Florida)

  • Jenna Oberstaller

    (University of South Florida)

  • Phaedra Thomas

    (University of South Florida)

  • Thomas D. Otto

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Glasgow)

  • Debora Casandra

    (University of South Florida)

  • Sandhya Boyapalle

    (University of South Florida)

  • Swamy R. Adapa

    (University of South Florida)

  • Shulin Xu

    (University of South Florida)

  • Katrina Button-Simons

    (University of Notre Dame)

  • Matthew Mayho

    (Wellcome Sanger Institute, Wellcome Genome Campus)

  • Julian C. Rayner

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge, Cambridge Biomedical Campus)

  • Michael T. Ferdig

    (University of Cambridge, Cambridge Biomedical Campus)

  • Rays H. Y. Jiang

    (University of South Florida)

  • John H. Adams

    (University of South Florida)

Abstract

The emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry out a large-scale forward-genetic phenotype screen in P. falciparum to identify genes allowing parasites to survive febrile temperatures. Screening identifies more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants are more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin include highly essential, conserved pathways associated with protein-folding, heat shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general are upregulated in response to heat shock, as are other Plasmodium genes with orthologs in plant and algal genomes. Plasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiont-derived genes in the parasite’s genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors.

Suggested Citation

  • Min Zhang & Chengqi Wang & Jenna Oberstaller & Phaedra Thomas & Thomas D. Otto & Debora Casandra & Sandhya Boyapalle & Swamy R. Adapa & Shulin Xu & Katrina Button-Simons & Matthew Mayho & Julian C. Ra, 2021. "The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24814-1
    DOI: 10.1038/s41467-021-24814-1
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    Cited by:

    1. Hui Min & Xiaoying Liang & Chengqi Wang & Junling Qin & Rachasak Boonhok & Azhar Muneer & Awtum M. Brashear & Xiaolian Li & Allen M. Minns & Swamy Rakesh Adapa & Rays H. Y. Jiang & Gang Ning & Yaming , 2024. "The DEAD-box RNA helicase PfDOZI imposes opposing actions on RNA metabolism in Plasmodium falciparum," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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