在肯尼亚儿童接受青蒿素联合疗法治疗后，恶性疟原虫中缺乏持续存在的K13突变。
Lack of K13 mutations in Plasmodium falciparum persisting after artemisinin combination therapy treatment of Kenyan children.
作者信息
Muwanguzi Julian, Henriques Gisela, Sawa Patrick, Bousema Teun, Sutherland Colin J, Beshir Khalid B
机构信息
Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK.
Human Health Division, International Centre of Insect Physiology and Ecology, Mbita Point, Western Kenya, Kenya.
出版信息
Malar J. 2016 Jan 22;15:36. doi: 10.1186/s12936-016-1095-y.
BACKGROUND
Studies in Southeast Asia reported a strong relationship between polymorphisms at the propeller domain of the Kelch 13 (K13) protein encoded by the Plasmodium falciparum k13 (pfk13) gene and delayed parasite clearance after artemisinin treatment. In Africa, P. falciparum remains susceptible and combination therapy regimens which include an artemisinin component display good efficacy. Using quantitative real-time PCR (qPCR), sub-microscopic persistence of P. falciparum has previously been reported in one-third of children treated with artemisinin combination therapy (ACT) in western Kenya. In this study, further investigation was made to evaluate whether these sub-microscopic residual parasites also harbour mutations at the propeller region of pfk13 and whether the mutations, if any, affect treatment outcome.
METHODS
The pfk13 propeller domain was genotyped in DNA samples obtained in 2009 from Kenyan children treated with artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Paired samples at pre-treatment (day 0) and day of treatment failure (day 28 or 42) for 32 patients with documented recurrent parasitaemia were available for genotyping. Additional day 3 DNA samples were available for 10 patients.
RESULTS
No mutation associated with artemisinin resistance in Southeast Asia was observed. Only one DP-treated patient harboured a non-synonymous mutation at codon 578 (A578S) of pfk13-propeller gene in the day 0 sample, but this allele was replaced by the wild-type (A578) form on day 3 and on the day of recurrent parasitaemia. The mutation at amino acid codon 578 showed no association with any phenotype. Polymorphisms in pfk13 were not responsible for parasite persistence and gametocyte carriage in the children treated with ACT.
CONCLUSION
This study contributes to the ongoing surveillance of suspected artemisinin resistance parasites in Africa by providing baseline prevalence of k13-propeller mutations in western Kenya with samples collected from a longitudinal study. Clinical Trials Registration NCT00868465.
背景
东南亚的研究报告称，恶性疟原虫k13（pfk13）基因编码的凯尔希13（K13）蛋白螺旋桨结构域的多态性与青蒿素治疗后寄生虫清除延迟之间存在密切关系。在非洲，恶性疟原虫仍然易感，包含青蒿素成分的联合治疗方案显示出良好的疗效。此前曾使用定量实时PCR（qPCR）报告称，在肯尼亚西部接受青蒿素联合疗法（ACT）治疗的儿童中，三分之一的儿童体内存在亚显微水平的恶性疟原虫持续感染。在本研究中，进一步调查评估了这些亚显微水平的残留寄生虫在pfk13螺旋桨区域是否也存在突变，以及这些突变（如果有的话）是否会影响治疗结果。
方法
对2009年从接受蒿甲醚-本芴醇（AL）和双氢青蒿素-哌喹（DP）治疗的肯尼亚儿童获得的DNA样本进行pfk13螺旋桨结构域基因分型。对32例有复发性寄生虫血症记录的患者，在治疗前（第0天）和治疗失败日（第28天或第42天）采集的配对样本可用于基因分型。另外10例患者有第3天的DNA样本。
结果
未观察到与东南亚青蒿素耐药相关的突变。仅1例接受DP治疗的患者在第0天的样本中，pfk13螺旋桨基因密码子578处存在非同义突变（A578S），但该等位基因在第3天和复发性寄生虫血症日被野生型（A578）形式取代。氨基酸密码子578处的突变与任何表型均无关联。pfk13的多态性与接受ACT治疗儿童体内寄生虫的持续存在和配子体携带情况无关。
结论
本研究通过对肯尼亚西部纵向研究收集的样本进行k13螺旋桨突变基线患病率调查，为非洲正在进行的疑似青蒿素耐药寄生虫监测做出了贡献。临床试验注册号：NCT00868465。
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