东南亚恶性疟原虫 falcipain-2a 多态性及其与青蒿素耐药性的关系。
Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance.
机构信息
Department of Entomology, Pennsylvania State University, University Park.
College of Basic Medical Sciences, China Medical University, Shenyang.
出版信息
J Infect Dis. 2018 Jul 2;218(3):434-442. doi: 10.1093/infdis/jiy188.
Abstract
BACKGROUND
Falcipain-2a ([FP2a] PF3D7_1115700) is a Plasmodium falciparum cysteine protease and hemoglobinase. Functional FP2a is required for potent activity of artemisinin, and in vitro selection for artemisinin resistance selected for an FP2a nonsense mutation.
METHODS
To investigate associations between FP2a polymorphisms and artemisinin resistance and to characterize the diversity of the enzyme in parasites from the China-Myanmar border, we sequenced the full-length FP2a gene in 140 P falciparum isolates collected during 2004-2011.
RESULTS
The isolates were grouped into 8 different haplotype groups. Haplotype group I appeared in samples obtained after 2008, coinciding with implementation of artemisinin-based combination therapy in this region. In functional studies, compared with wild-type parasites, the FP2a haplotypes demonstrated increased ring survival, and all haplotype groups exhibited significantly reduced FP2a activity, with group I showing the slowest protease kinetics and reduced parasite fitness.
CONCLUSIONS
These results suggest that altered hemoglobin digestion due to FP2a mutations may contribute to artemisinin resistance.
摘要
背景
裂殖体 2a 蛋白酶 ([FP2a] PF3D7_1115700) 是疟原虫裂殖体的一种半胱氨酸蛋白酶和血红蛋白酶。功能性 FP2a 是青蒿素发挥强效作用所必需的，而针对青蒿素耐药性的体外选择则导致 FP2a 无义突变。
方法
为了研究 FP2a 多态性与青蒿素耐药性之间的关联，并对来自中缅边境地区寄生虫中的该酶的多样性进行特征描述，我们对 2004 年至 2011 年间采集的 140 株恶性疟原虫分离株进行了全长 FP2a 基因测序。
结果
这些分离株被分为 8 个不同的单倍型组。单倍型组 I 出现在 2008 年后采集的样本中，这与该地区实施青蒿素为基础的联合疗法相吻合。在功能研究中，与野生型寄生虫相比，FP2a 单倍型显示出更高的环生存能力，所有单倍型组均表现出显著降低的 FP2a 活性，其中组 I 显示出最慢的蛋白酶动力学和降低的寄生虫适应性。
结论
这些结果表明，FP2a 突变导致的血红蛋白消化改变可能有助于青蒿素耐药性的产生。
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本文引用的文献
1
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2
The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study.大湄公河次区域青蒿素耐药恶性疟原虫的传播：一项分子流行病学观察性研究。
Lancet Infect Dis. 2017 May;17(5):491-497. doi: 10.1016/S1473-3099(17)30048-8. Epub 2017 Feb 2.
3
Limited genetic diversity in the PvK12 Kelch protein in Plasmodium vivax isolates from Southeast Asia.东南亚间日疟原虫分离株中PvK12 Kelch蛋白的遗传多样性有限。
Malar J. 2016 Nov 8;15(1):537. doi: 10.1186/s12936-016-1583-0.
4
A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study.耐哌喹恶性疟原虫疟疾的替代标志物：一项表型-基因型关联研究。
Lancet Infect Dis. 2017 Feb;17(2):174-183. doi: 10.1016/S1473-3099(16)30415-7. Epub 2016 Nov 3.
5
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Lancet Infect Dis. 2017 Feb;17(2):164-173. doi: 10.1016/S1473-3099(16)30409-1. Epub 2016 Nov 3.
6
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7
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Microbiol Spectr. 2016 Jun;4(3). doi: 10.1128/microbiolspec.EI10-0013-2016.
8
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9
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J Cell Sci. 2016 Jan 15;129(2):406-16. doi: 10.1242/jcs.178830. Epub 2015 Dec 16.
10
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