Abstract:
Plasmodium parasites, the causal agents of malaria, are eukaryotic organisms that obligately undergo sexual recombination within mosquitoes. In low transmission settings, parasites recombine with themselves, and the clonal lineage is propagated rather than broken up by outcrossing. We investigated whether stochastic/neutral factors drive the persistence and abundance of Plasmodium falciparum clonal lineages in Guyana, a country with relatively low malaria transmission, but the only setting in the Americas in which an important artemisinin resistance mutation (pfk13 C580Y) has been observed. We performed whole genome sequencing on 1,727 Plasmodium falciparum samples collected from infected patients across a five-year period (2016-2021). We characterized the relatedness between each pair of monoclonal infections (n = 1,409) through estimation of identity-by-descent (IBD) and also typed each sample for known or candidate drug resistance mutations. A total of 160 multi-isolate clones (mean IBD ≥ 0.90) were circulating in Guyana during the study period, comprising 13 highly related clusters (mean IBD ≥ 0.40). In the five-year study period, we observed a decrease in frequency of a mutation associated with artemisinin partner drug (piperaquine) resistance (pfcrt C350R) and limited co-occurence of pfcrt C350R with duplications of plasmepsin 2/3, an epistatic interaction associated with piperaquine resistance. We additionally observed 61 nonsynonymous substitutions that increased markedly in frequency over the study period as well as a novel pfk13 mutation (G718S). However, P. falciparum clonal dynamics in Guyana appear to be largely driven by stochastic factors, in contrast to other geographic regions, given that clones carrying drug resistance polymorphisms do not demonstrate enhanced persistence or higher abundance than clones carrying polymorphisms of comparable frequency that are unrelated to resistance. The use of multiple artemisinin combination therapies in Guyana may have contributed to the disappearance of the pfk13 C580Y mutation.
摘要:
疟原虫寄生虫,疟疾的病原体,是真核生物,它们在蚊子内强制进行性重组。在低传输设置中,寄生虫与自己重组,克隆谱系是繁殖的,而不是通过异交来分裂的。我们调查了随机/中性因素是否驱动圭亚那恶性疟原虫克隆谱系的持久性和丰度,一个疟疾传播相对较低的国家,但是在美洲,唯一一个重要的青蒿素抗性突变(pfk13C580Y)被观察到。我们对5年(2016-2021年)从感染患者中收集的1,727例恶性疟原虫样本进行了全基因组测序。我们通过估计血统身份(IBD)来表征每对单克隆感染(n=1,409)之间的相关性,并对每个样本进行了已知或候选耐药性突变的分型。在研究期间,圭亚那共有160个多分离株克隆(平均IBD≥0.90)循环,包括13个高度相关的簇(平均IBD≥0.40)。在五年的学习期间,我们观察到与青蒿素伴侣药物(哌喹)耐药(pfcrtC350R)相关的突变频率降低,并且pfcrtC350R与plasmepsin2/3重复的有限共存,plasmepsin2/3是一种与哌喹耐药相关的上位相互作用.我们还观察到61个非同义取代,在研究期间频率显着增加,以及一个新的pfk13突变(G718S)。然而,圭亚那的恶性疟原虫克隆动力学似乎在很大程度上是由随机因素驱动的,与其他地理区域相比,考虑到携带耐药多态性的克隆与携带与耐药无关的相当频率的多态性的克隆相比,没有表现出增强的持久性或更高的丰度。在圭亚那使用多种青蒿素组合疗法可能导致pfk13C580Y突变的消失。