K13-Mediated Reduced Susceptibility to Artemisinin in Plasmodium falciparum Is Overlaid on a Trait of Enhanced DNA Damage Repair

• Published in: Cell reports (Cambridge) 2020-08, Vol.32 (5), p.107996-107996, Article 107996
• Main Authors: Xiong, Aoli, Prakash, Prem, Gao, Xiaohong, Chew, Marvin, Tay, Ian Jun Jie, Woodrow, Charles J., Engelward, Bevin P., Han, Jongyoon, Preiser, Peter R.
• Format: Article
• Language: English
• Subjects: Africa; Artemisinins - pharmacology; Asia, Southeastern; DNA Damage; DNA Repair - drug effects; Drug Resistance - drug effects; Genotype; Geography; Humans; Life Cycle Stages - drug effects; Phenotype; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium falciparum - growth & development; Plasmodium falciparum - isolation & purification; Protein Domains; Protozoan Proteins - chemistry; Protozoan Proteins - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107996

Southeast Asia has been the hotbed for the development of drug-resistant malaria parasites, including those with resistance to artemisinin combination therapy. While mutations in the kelch propeller domain (K13 mutations) are associated with artemisinin resistance, a range of evidence suggests that other factors are critical for the establishment and subsequent transmission of resistance in the field. Here, we perform a quantitative analysis of DNA damage and repair in the malaria parasite Plasmodium falciparum and find a strong link between enhanced DNA damage repair and artemisinin resistance. This experimental observation is further supported when variations in seven known DNA repair genes are found in resistant parasites, with six of these mutations being associated with K13 mutations. Our data provide important insights on confounding factors that are important for the establishment and spread of artemisinin resistance and may explain why resistance has not yet arisen in Africa. [Display omitted] •High-throughput MalariaCometChip to measure DNA damage level in P. falciparum•Subpopulation of Cambodian isolates possess enhanced DNA damage repair•Important link between enhanced DNA damage repair and artemisinin resistance Southeast Asia (SEA) has been the breeding ground for malaria drug resistance, including resistance to artemisinin, the first-line anti-malarial drug. In this study, Xiong et al. find a relationship between DNA damage repair and artemisinin resistance in SEA, leading to insights on the establishment and spread of current artemisinin resistance.