Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response
Lei Zhua, Rob W. van der Pluijmb c d, Michal Kucharskia, Sourav Nayaka, Jaishree Tripathia, Nicholas John Whitec d, Nicholas Dayc d, Abul Faize f, Aung Pyae Phyoc g, Chanaki Amaratungac d h, Dysoley Leki, Elizabeth A. Ashleyc j, François Henry Nostenc k, Frank M. Smithuisc g, Hagai Ginsburgl, Lorenz von Seidleinc d, Khin Linm, Mallika Imwongd n, Kesinee Chotivanichd n, Mayfong Mayxayj o, Mehul Dhordac d p, Hoang Chau Nguyenq, Thuy-Nhien Nguyenq, Olivo Miottoc d r s, Paul N. Newtonc j, Podjanee Jittamalad t, Rupam Tripurac d, Sasithon Pukrittayakameed m u, Thomas Julian Petoc d, Tran Tinh Hient and 2 others
- aSchool of Biological Sciences, Nanyang Technological University, Singapore, Singapore
- bCenter of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- cCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- dMahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- eMalaria Research Group and Dev Care Foundation, Dhaka, Bangladesh
- fRamu Upazila Health Complex, Cox's Bazar, Bangladesh
- gMyanmar Oxford Clinical Research Unit, Yangon, Myanmar
- hLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
- iNational Centre for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
- jLao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Vientiane, Laos
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Abstract
The emergence and spread of artemisinin-resistant Plasmodium falciparum, first in the Greater Mekong Subregion (GMS), and now in East Africa, is a major threat to global malaria elimination ambitions. To investigate the artemisinin resistance mechanism, transcriptome analysis was conducted of 577 P. falciparum isolates collected in the GMS between 2016-2018. A specific artemisinin resistance-associated transcriptional profile was identified that involves a broad but discrete set of biological functions related to proteotoxic stress, host cytoplasm remodelling, and REDOX metabolism. The artemisinin resistance-associated transcriptional profile evolved from initial transcriptional responses of susceptible parasites to artemisinin. The genetic basis for this adapted response is likely to be complex.