Artemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival

Sachel Mok, Barbara H. Stokes, Nina F. Gnädig, Leila S. Ross, Tomas Yeo, Chanaki Amaratunga, Erik Allman, Lev Solyakov, Andrew R. Bottrill, Jaishree Tripathi, Rick M. Fairhurst, Manuel Llinás, Zbynek Bozdech, Andrew B. Tobin and David A. Fidock ()
Additional contact information
Sachel Mok: Columbia University Irving Medical Center
Barbara H. Stokes: Columbia University Irving Medical Center
Nina F. Gnädig: Columbia University Irving Medical Center
Leila S. Ross: Columbia University Irving Medical Center
Tomas Yeo: Columbia University Irving Medical Center
Chanaki Amaratunga: National Institutes of Health
Erik Allman: Pennsylvania State University
Lev Solyakov: University of Leicester
Andrew R. Bottrill: University of Leicester
Jaishree Tripathi: Nanyang Technological University
Rick M. Fairhurst: National Institutes of Health
Manuel Llinás: Pennsylvania State University
Zbynek Bozdech: Nanyang Technological University
Andrew B. Tobin: University of Glasgow
David A. Fidock: Columbia University Irving Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The emergence and spread of artemisinin resistance, driven by mutations in Plasmodium falciparum K13, has compromised antimalarial efficacy and threatens the global malaria elimination campaign. By applying systems-based quantitative transcriptomics, proteomics, and metabolomics to a panel of isogenic K13 mutant or wild-type P. falciparum lines, we provide evidence that K13 mutations alter multiple aspects of the parasite’s intra-erythrocytic developmental program. These changes impact cell-cycle periodicity, the unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. K13-mediated artemisinin resistance in the Cambodian Cam3.II line was reversed by atovaquone, a mitochondrial electron transport chain inhibitor. These results suggest that mitochondrial processes including damage sensing and anti-oxidant properties might augment the ability of mutant K13 to protect P. falciparum against artemisinin action by helping these parasites undergo temporary quiescence and accelerated growth recovery post drug elimination.

Date: 2021
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DOI: 10.1038/s41467-020-20805-w

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