The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background

Lei Zhu, Jaishree Tripathi, Frances Maureen Rocamora, Olivo Miotto, Rob Pluijm, Till S. Voss, Sachel Mok, Dominic P. Kwiatkowski, François Nosten, Nicholas P. J. Day, Nicholas J. White, Arjen M. Dondorp and Zbynek Bozdech ()
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Lei Zhu: Nanyang Technological University
Jaishree Tripathi: Nanyang Technological University
Frances Maureen Rocamora: Nanyang Technological University
Olivo Miotto: Mahidol University
Rob Pluijm: Mahidol University
Till S. Voss: Swiss Tropical and Public Health Institute
Sachel Mok: Columbia University
Dominic P. Kwiatkowski: Mahidol University
François Nosten: Mahidol University
Nicholas P. J. Day: Mahidol University
Nicholas J. White: Mahidol University
Arjen M. Dondorp: Mahidol University
Zbynek Bozdech: Nanyang Technological University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The predisposition of parasites acquiring artemisinin resistance still remains unclear beyond the mutations in Pfk13 gene and modulation of the unfolded protein response pathway. To explore the chain of casualty underlying artemisinin resistance, we reanalyze 773 P. falciparum isolates from TRACI-study integrating TWAS, GWAS, and eQTL analyses. We find the majority of P. falciparum parasites are transcriptomically converged within each geographic site with two broader physiological profiles across the Greater Mekong Subregion (GMS). We report 8720 SNP-expression linkages in the eastern GMS parasites and 4537 in the western. The minimal overlap between them suggests differential gene regulatory networks facilitating parasite adaptations to their unique host environments. Finally, we identify two genetic and physiological backgrounds associating with artemisinin resistance in the GMS, together with a farnesyltransferase protein and a thioredoxin-like protein which may act as vital intermediators linking the Pfk13 C580Y mutation to the prolonged parasite clearance time.

Date: 2018
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DOI: 10.1038/s41467-018-07588-x

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