Artemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 22, 2021
- Source ID
- 10.1038/s41467-020-20805-w
Entities
People
- Andrew B Tobin
- Andrew R. Bottrill
- Barbara H Stokes
- Chanaki Amaratunga
- David A. Fidock
- Erik Allman
- Jaishree Tripathi
- Leila S. Ross
- Lev Solyakov
- Manuel Llinás
- Nina F Gnädig
- Rick M. Fairhurst
- Sachel Mok
- Tomas Yeo
- Zbynek Bozdech
Organizations
- Human Frontier Science Program
- National Institute of Allergy and Infectious Diseases
- United States Department of Defense