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

Aoli Xiong,Prem Prakash,Xiaohong Gao,Marvin Chew,Ian Jun Jie Tay,Charles J Woodrow,Bevin P Engelward,Jongyoon Han,Peter R Preiser

doi:10.1016/j.celrep.2020.107996

Abstract

SummarySoutheast 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.

Highlights

Malaria remains a severe public health burden, causing an estimated 228 million cases and about 0.4 million deaths in 2018 (World Health Organization, [WHO], 2019)
Detection of Artesunate-Induced DNA Damage in Early and Late Stage P. falciparum Using Alkaline malariaCometChip Previous work has suggested that artesunate induces DNA damage in the P. falciparum parasite via the formation of reactive oxygen species (ROS) (Gopalakrishnan and Kumar, 2015)
To obtain a more comprehensive understanding of artesunate-induced DNA damage, we first investigated the effect of artesunate, activated with ferrous heme or non-heme exogenous Fe2+, on purified DNA using more physiologically relevant concentrations

Summary

Introduction

Malaria remains a severe public health burden, causing an estimated 228 million cases and about 0.4 million deaths in 2018 (World Health Organization, [WHO], 2019). Parasites resistant to artemisinin have emerged in Southeast Asia (SEA), leading to significant selection pressure on the partner drugs used in ACTs (Amaratunga et al, 2014). There is evidence that resistance to piperaquine, the partner drug used in Cambodia, is developing (Amaratunga et al, 2016; Chaorattanakawee et al, 2015; Duru et al, 2015; Leang et al, 2015; Witkowski et al, 2017). Evidence shows >5% prevalence of artemisinin resistance associated K13 mutations in Rwanda, Guyana, and Papua New Guinea, but the clearance and efficacy of first-line treatment in the regions have not yet been affected (WHO, 2019)

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