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

• Published in: Nature communications Vol. 9; no. 1; pp. 5158 - 13
• Main Authors: Zhu, Lei, Tripathi, Jaishree, Rocamora, Frances Maureen, Miotto, Olivo, van der Pluijm, Rob, Voss, Till S., Mok, Sachel, Kwiatkowski, Dominic P., Nosten, François, Day, Nicholas P. J., White, Nicholas J., Dondorp, Arjen M., Bozdech, Zbynek
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 45/43; 45/61; 631/208/205/2138; 631/326/22/1434; 631/326/417/2551; 692/699/255/1629; Adaptation; Antimalarials - pharmacology; Antimalarials - therapeutic use; Artemisinin; Artemisinins - pharmacology; Artemisinins - therapeutic use; Chromosome Mapping; DNA, Protozoan; Drug Resistance - genetics; Farnesyltransferase; Farnesyltranstransferase - genetics; Gene Expression; Gene Regulatory Networks; Genes, Protozoan - genetics; Geography; Humanities and Social Sciences; Humans; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Molecular Epidemiology; multidisciplinary; Mutation; Mutation - drug effects; Parasites; Physiology; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium falciparum - isolation & purification; Protein folding; Proteins; Protozoan Proteins - genetics; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Thioredoxin; Thioredoxins; Transcriptome; Vector-borne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07588-x

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. Mechanisms underlying increasing artemisinin resistance of Plasmodium in Southeast Asia remain unclear. Here, Zhu et al. integrate TWAS, GWAS and eQTL analyses for 773 P. falciparum isolates and identify genetic and transcriptomic backgrounds to artemisinin resistance.