Population genomics and transcriptomics of Plasmodium falciparum in Cambodia and Vietnam uncover key components of the artemisinin resistance genetic background

Sourav Nayak, Thomas J. Peto, Michal Kucharski, Rupam Tripura, James J. Callery, Duong Tien Quang Huy, Mathieu Gendrot, Dysoley Lek, Ho Dang Trung Nghia, Rob W. Pluijm, Nguyen Dong, Le Thanh Long, Ranitha Vongpromek, Huy Rekol, Nguyen Hoang Chau, Olivo Miotto, Mavuto Mukaka, Mehul Dhorda, Lorenz Seidlein, Mallika Imwong, Xavier Roca, Nicholas P. J. Day, Nicholas J. White, Arjen M. Dondorp () and Zbynek Bozdech ()
Additional contact information
Sourav Nayak: Nanyang Technological University
Thomas J. Peto: Mahidol University
Michal Kucharski: Nanyang Technological University
Rupam Tripura: Mahidol University
James J. Callery: Mahidol University
Duong Tien Quang Huy: Nanyang Technological University
Mathieu Gendrot: Nanyang Technological University
Dysoley Lek: Entomology and Malaria Control
Ho Dang Trung Nghia: Hospital for Tropical Diseases
Rob W. Pluijm: Mahidol University
Nguyen Dong: Khanh Hoa Hospital for Tropical diseases
Le Thanh Long: Phuoc Long Hospital
Ranitha Vongpromek: Mahidol University
Huy Rekol: Amsterdam Institute for Global Health and Development
Nguyen Hoang Chau: National Institute for Public Health
Olivo Miotto: Mahidol University
Mavuto Mukaka: Mahidol University
Mehul Dhorda: Mahidol University
Lorenz Seidlein: Mahidol University
Mallika Imwong: Mahidol University
Xavier Roca: Nanyang Technological University
Nicholas P. J. Day: Mahidol University
Nicholas J. White: Mahidol University
Arjen M. Dondorp: Mahidol University
Zbynek Bozdech: Nanyang Technological University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The emergence of Plasmodium falciparum parasites resistant to artemisinins compromises the efficacy of Artemisinin Combination Therapies (ACTs), the global first-line malaria treatment. Artemisinin resistance is a complex genetic trait in which nonsynonymous SNPs in PfK13 cooperate with other genetic variations. Here, we present population genomic/transcriptomic analyses of P. falciparum collected from patients with uncomplicated malaria in Cambodia and Vietnam between 2018 and 2020. Besides the PfK13 SNPs, several polymorphisms, including nonsynonymous SNPs (N1131I and N821K) in PfRad5 and an intronic SNP in PfWD11 (WD40 repeat-containing protein on chromosome 11), appear to be associated with artemisinin resistance, possibly as new markers. There is also a defined set of genes whose steady-state levels of mRNA and/or splice variants or antisense transcripts correlate with artemisinin resistance at the base level. In vivo transcriptional responses to artemisinins indicate the resistant parasite’s capacity to decelerate its intraerythrocytic developmental cycle (IDC), which can contribute to the resistant phenotype. During this response, PfRAD5 and PfWD11 upregulate their respective alternatively/aberrantly spliced isoforms, suggesting their contribution to the protective response to artemisinins. PfRAD5 and PfWD11 appear under selective pressure in the Greater Mekong Sub-region over the last decade, suggesting their role in the genetic background of the artemisinin resistance.

Date: 2024
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DOI: 10.1038/s41467-024-54915-6

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