Medical Research Council at London School of Hygiene and Tropical Medicine, Fajara, The Gambia.
University of Ghana, Legon, Accra, Ghana.
J Antimicrob Chemother. 2022 Oct 28;77(11):2946-2955. doi: 10.1093/jac/dkac244.
Artemether/lumefantrine is the most commonly used artemisinin-based combination treatment (ACT) for malaria in sub-Saharan Africa. Drug resistance to ACT components is a major threat to malaria elimination efforts. Therefore, rigorous monitoring of drug efficacy is required for adequate management of malaria and to sustain the effectiveness of ACTs.
This study identified and described genomic loci that correlate with differences in ex vivo responses of natural Plasmodium falciparum isolates from The Gambia to antimalarial drugs.
Natural P. falciparum isolates from The Gambia were assayed for IC50 responses to four antimalarial drugs (artemether, dihydroartemisinin, amodiaquine and lumefantrine). Genome-wide SNPs from 56 of these P. falciparum isolates were applied to mixed-model regression and network analyses to determine linked loci correlating with drug responses. Genomic regions of shared haplotypes and positive selection within and between Gambian and Cambodian P. falciparum isolates were mapped by identity-by-descent (IBD) analysis of 209 genomes.
SNPs in 71 genes, mostly involved in stress and drug resistance mechanisms correlated with drug responses. Additionally, erythrocyte invasion and permeability loci, including merozoite surface proteins (Pfdblmsp, Pfsurfin), and high-molecular-weight rhoptry protein 2 (Pfrhops2) were correlated with responses to multiple drugs. Haplotypes of pfdblmsp2 and known drug resistance loci (pfaat1, pfcrt and pfdhfr) from The Gambia showed high IBD with those from Cambodia, indicating co-ancestry, with significant linkage disequilibrium between their alleles.
Multiple linked genic loci correlating with drug response phenotypes suggest a genomic backbone may be under selection by antimalarials. This calls for further analysis of molecular pathways to drug resistance in African P. falciparum.
青蒿琥酯/咯萘啶是撒哈拉以南非洲地区最常用的青蒿素类复方疗法（ACT）治疗疟疾的药物。ACT 成分的耐药性是消除疟疾工作的主要威胁。因此，需要严格监测药物疗效，以充分管理疟疾并维持 ACT 的有效性。
本研究鉴定并描述了与冈比亚天然疟原虫分离株对抗疟药物的体外反应差异相关的基因组基因座。
对来自冈比亚的天然疟原虫分离株进行了四种抗疟药物（青蒿琥酯、双氢青蒿素、阿莫地喹和咯萘啶）的 IC50 反应测定。对 56 株疟原虫分离株的全基因组 SNP 进行混合模型回归和网络分析，以确定与药物反应相关的连锁基因座。通过对 209 个基因组的同源性分析（IBD），对冈比亚和柬埔寨疟原虫分离株的共享单倍型和正选择的基因组区域进行了映射。
与药物反应相关的 71 个基因中的 SNP，主要涉及应激和耐药机制。此外，红细胞入侵和通透性基因座，包括裂殖子表面蛋白（PfDBLMsp、PfSURFIN）和高相对分子质量的棒状体蛋白 2（PfRHOPs2）与对多种药物的反应相关。来自冈比亚的 pfdblmsp2 单倍型和已知的耐药基因座（pfaat1、pfcrt 和 pfdhfr）与来自柬埔寨的单倍型显示出高度的 IBD，表明它们具有共同的祖先，其等位基因之间存在显著的连锁不平衡。
与药物反应表型相关的多个连锁基因座表明，基因组可能正在受到抗疟药物的选择。这呼吁进一步分析非洲疟原虫对药物的分子途径。
