恶性疟原虫的遗传因素而非宿主因素可能导致加纳对 ACT 的耐药性。
Plasmodium falciparum genetic factors rather than host factors are likely to drive resistance to ACT in Ghana.
机构信息
West African Center for Cell Biology of Infectious Pathogens, University of Ghana, P. O. Box LG54, Legon, Ghana.
Epidemiology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, P. O. Box LG581, Legon, Ghana.
出版信息
Malar J. 2020 Jul 15;19(1):255. doi: 10.1186/s12936-020-03320-7.
BACKGROUND
Artemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine. Plasmodium falciparum isolates with reduced susceptibility to these partner drugs may affect treatment outcome. Mutations in pfmdr1 gene is linked to reduced parasite susceptibility to amodiaquine and lumefantrine. In addition, the potency of the partner drugs in vivo depends on the metabolism by the cytochrome P450 (CYP) enzyme in the host. Mutations in the CYP2C8 and CYP3A4 genes are linked to reduced metabolism of amodiaquine and lumefantrine in vitro, respectively. This study investigated the host and parasite genetic factors affecting the susceptibility of the malaria parasite to ACT partner drugs.
METHODS
Archived samples from 240 patients age ≤ 9 years participating in anti-malarial drug resistance survey in Ghana, and given artemether with lumefantrine (AL) or artesunate with amodiaquine (AA), were selected and analysed. Polymerase chain reaction (PCR) followed by Sanger sequencing was used to determine the polymorphisms in CYP2C8, CYP3A4 and pfmdr1 genes.
RESULTS
For CYP3A4, all had wild type alleles, suggesting that the hosts are good metabolizers of lumefantrine. For CYP2C8 60% had wild type alleles, 35% heterozygous and 5% homozygous recessive alleles suggesting efficient metabolism of amodiaquine by the hosts. For pfmdr1 gene, at codon 86, 95% were wild type (N86) and 5% mutant (Y86). For codon 184, 36% were wild type (Y184) and 64% mutant (F184) while for codons 1034, 1042 and 1246, 100% (all) were wild type. The high prevalence of N86-F184-D1246 haplotype (NFD) suggest presence of parasites with reduced susceptibility to lumefantrine and not amodiaquine. Delayed clearance was observed in individuals with mutations in the pfmdr1 gene and not cytochrome 450 gene. Both synonymous and non-synonymous mutations were observed in the pfmdr1 at low prevalence.
CONCLUSION
The outcome of this study indicates that the parasite's genetic factors rather than the host's are likely to drive resistance to ACT in Ghana.
背景
目前加纳使用的青蒿素复方疗法（ACT）联合用药有青蒿琥酯、阿莫地喹和哌喹。对这些联合用药具有较低敏感性的恶性疟原虫可能会影响治疗效果。 pfmdr1 基因突变与恶性疟原虫对阿莫地喹和青蒿琥酯的敏感性降低有关。此外，联合用药在体内的效力取决于宿主细胞色素 P450（CYP）酶的代谢。CYP2C8 和 CYP3A4 基因突变分别与阿莫地喹和青蒿琥酯在体外的代谢减少有关。本研究调查了影响恶性疟原虫对 ACT 联合用药敏感性的宿主和寄生虫遗传因素。
方法
选择并分析了来自加纳抗疟药耐药性调查中 240 名年龄≤9 岁的患者的存档样本，这些患者接受了青蒿琥酯加哌喹（AL）或青蒿琥酯加阿莫地喹（AA）治疗。聚合酶链反应（PCR）后进行 Sanger 测序，以确定 CYP2C8、CYP3A4 和 pfmdr1 基因的多态性。
结果
对于 CYP3A4，所有患者均具有野生型等位基因，这表明宿主是青蒿琥酯的良好代谢者。对于 CYP2C8，60%为野生型等位基因，35%为杂合子，5%为纯合隐性等位基因，表明宿主对阿莫地喹的代谢效率较高。对于 pfmdr1 基因，86 位密码子 95%为野生型（N86），5%为突变型（Y86）。184 位密码子 36%为野生型（Y184），64%为突变型（F184），而 1034、1042 和 1246 位密码子 100%（均）为野生型。N86-F184-D1246 单倍型（NFD）的高流行率表明存在对青蒿琥酯敏感性降低的寄生虫，而不是对阿莫地喹的敏感性降低。pfmdr1 基因突变而不是细胞色素 450 基因突变导致清除时间延迟。pfmdr1 中观察到同义和非同义突变，但发生率较低。
结论
本研究结果表明，加纳 ACT 耐药性可能是由寄生虫的遗传因素而非宿主的遗传因素驱动的。
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