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

Zhang, M. et al. (2021) The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite. Nature Communications, 12, 4563. (doi: 10.1038/s41467-021-24814-1) (PMID:34315897) (PMCID:PMC8316339)

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.

• Item Type: Articles
• Additional Information: This work was supported by the National Institutes of Health grants R01 AI094973 and R01 AI117017 (J.H.A.), F32 AI112271 (J.O.), and the Wellcome Trust grant 098051 (J.C.R.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas
• Authors: Zhang, M., Wang, C., Oberstaller, J., Thomas, P., Otto, T. D., Casandra, D., Boyapalle, S., Adapa, S. R., Xu, S., Button-Simons, K., Mayho, M., Rayner, J. C., Ferdig, M. T., Jiang, R. H. Y., and Adams, J. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 4563
• Publisher Policy: Reproduced under a Creative Commons License