Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13

Gnädig, N. F. et al. (2020) Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13. PLoS Pathogens, 16(4), e1008482. (doi: 10.1371/journal.ppat.1008482) (PMID:32310999) (PMCID:PMC7192513)

Abstract

The emergence of artemisinin (ART) resistance in Plasmodium falciparum intra-erythrocytic parasites has led to increasing treatment failure rates with first-line ART-based combination therapies in Southeast Asia. Decreased parasite susceptibility is caused by K13 mutations, which are associated clinically with delayed parasite clearance in patients and in vitro with an enhanced ability of ring-stage parasites to survive brief exposure to the active ART metabolite dihydroartemisinin. Herein, we describe a panel of K13-specific monoclonal antibodies and gene-edited parasite lines co-expressing epitope-tagged versions of K13 in trans. By applying an analytical quantitative imaging pipeline, we localize K13 to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes. These latter structures form at the parasite plasma membrane and traffic hemoglobin to the digestive vacuole wherein artemisinin-activating heme moieties are released. We also provide evidence of K13 partially localizing near the parasite mitochondria upon treatment with dihydroartemisinin. Immunoprecipitation data generated with K13-specific monoclonal antibodies identify multiple putative K13-associated proteins, including endoplasmic reticulum-resident molecules, mitochondrial proteins, and Rab GTPases, in both K13 mutant and wild-type isogenic lines. We also find that mutant K13-mediated resistance is reversed upon co-expression of wild-type or mutant K13. These data help define the biological properties of K13 and its role in mediating P. falciparum resistance to ART treatment.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stokes, Ms Barbara
• Authors: Gnädig, N. F., Stokes, B. H., Edwards, R. L., Kalantarov, G. F., Heimsch, K. C., Kuderjavy, M., Crane, A., Lee, M. C. S., Straimer, J., Becker, K., Trakht, I. N., Odom John, A. R., Mok, S., and Fidock, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS Pathogens
• Publisher: Public Library of Science
• ISSN: 1553-7366
• ISSN (Online): 1553-7374
• Published Online: 20 April 2020
• Copyright Holders: Copyright © 2020 Gnädig et al.
• First Published: First published in PLoS Pathogens 16(4): e1008482
• Publisher Policy: Reproduced under a Creative Commons License