Balanced impacts of fitness and drug pressure on the evolution of PfMDR1 polymorphisms in Plasmodium falciparum.
Balanced impacts of fitness and drug pressure on the evolution of PfMDR1 polymorphisms in Plasmodium falciparum.
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DOI：
10.1186/s12936-021-03823-x
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发表时间：
2021-06-30
期刊：
影响因子：
3
通讯作者：
Rosenthal PJ
中科院分区：
文献类型：
--
作者：
Duvalsaint M;Conrad MD;Tukwasibwe S;Tumwebaze PK;Legac J;Cooper RA;Rosenthal PJ
抗疟疾药物的耐药可能受到耐药寄生虫适应性下降的限制。产生耐药性的重要因素是恶性疟原虫假定的药物转运体PfMDR1的突变。我们评估了两种常见的PfMDR1多态性（与多种药物敏感性相关的N86Y和对药物敏感性没有明显影响的Y184F）对体外适合度的影响，以研究抗性介质与寄生虫适合度之间的关系，并在竞争培养实验中以相对生长来衡量。表达所有PfMDR1 N86Y和Y184F单倍型的NF10恶性疟原虫系共培养40天，每4天通过焦磷酸测序对培养物的基因组成进行表征。研究了抗疟药培养对不同单倍型生长的影响。最后，尝试对含有另一种常见多态性PfMDR1 D1246Y的恶性疟原虫进行工程改造。共培养结果如下：固定野生型（WT） Y184 （N86/Y184 vs. 86Y/Y184）后，寄生型WT与86突变体处于平衡状态。固定突变体184F （N86/184F vs. 86Y/184F）时，86号突变体过度生长WT。固定突变体N86 （N86/Y184 vs. N86/184F）时，184号突变体过度生长WT。突变体86Y固定后（86Y/Y184 vs. 86Y/184F）， WT和突变体86处于平衡状态。携带双WT的寄生物与双突变体处于平衡状态，但86Y/Y184超过了N86/184F。总体而言，WT N86/突变体184F寄生虫比其他所有单倍型的寄生虫更不适合。为另一种突变PfMDR1 1246Y设计的寄生虫在培养中不稳定，随着时间的推移会恢复到WT。因此，N86 WT与Y184 WT在一起时是稳定的，但与突变体184F在一起时会产生适应度成本。在有氯喹存在的环境中培养有利于86Y突变体寄生虫，而在有甲苯胺存在的环境中培养有利于N86 WT寄生虫；哌喹的影响最小。这些结果与乌干达田间分离株的结果一致，提示了单倍型变化的原因，并强调了药物压力和适应性之间的相互作用，这种相互作用正在指导恶性疟原虫抗性介导单倍型的进化。
Anti-malarial drug resistance may be limited by decreased fitness in resistant parasites. Important contributors to resistance are mutations in the Plasmodium falciparum putative drug transporter PfMDR1. Impacts on in vitro fitness of two common PfMDR1 polymorphisms, N86Y, which is associated with sensitivity to multiple drugs, and Y184F, which has no clear impact on drug sensitivity, were evaluated to study associations between resistance mediators and parasite fitness, measured as relative growth in competitive culture experiments. NF10 P. falciparum lines engineered to represent all PfMDR1 N86Y and Y184F haplotypes were co-cultured for 40 days, and the genetic make-up of the cultures was characterized every 4 days by pyrosequencing. The impacts of culture with anti-malarials on the growth of different haplotypes were also assessed. Lastly, the engineering of P. falciparum containing another common polymorphism, PfMDR1 D1246Y, was attempted. Co-culture results were as follows. With wild type (WT) Y184 fixed (N86/Y184 vs. 86Y/Y184), parasites WT and mutant at 86 were at equilibrium. With mutant 184 F fixed (N86/184F vs. 86Y/184F), mutants at 86 overgrew WT. With WT N86 fixed (N86/Y184 vs. N86/184F), WT at 184 overgrew mutants. With mutant 86Y fixed (86Y/Y184 vs. 86Y/184F), WT and mutant at 86 were at equilibrium. Parasites with the double WT were in equilibrium with the double mutant, but 86Y/Y184 overgrew N86/184F. Overall, WT N86/mutant 184F parasites were less fit than parasites with all other haplotypes. Parasites engineered for another mutation, PfMDR1 1246Y, were unstable in culture, with reversion to WT over time. Thus, the N86 WT is stable when accompanied by the Y184 WT, but incurs a fitness cost when accompanied by mutant 184F. Culturing in the presence of chloroquine favored 86Y mutant parasites and in the presence of lumefantrine favored N86 WT parasites; piperaquine had minimal impact. These results are consistent with those for Ugandan field isolates, suggest reasons for varied haplotypes, and highlight the interplay between drug pressure and fitness that is guiding the evolution of resistance-mediating haplotypes in P. falciparum.
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影响因子：
6.4
作者：
Nsobya, Samuel L.;Kiggundu, Moses;Rosenthal, Philip J.
通讯作者：
Rosenthal, Philip J.
DOI：
10.4269/ajtmh.15-0007
发表时间：
2015-09
期刊：
The American journal of tropical medicine and hygiene
影响因子：
--
作者：
Cui L;Mharakurwa S;Ndiaye D;Rathod PK;Rosenthal PJ
通讯作者：
Rosenthal PJ
影响因子：
4.9
作者：
Nair, Shalini;Li, Xue;Anderson, Tim J. C.
通讯作者：
Anderson, Tim J. C.
影响因子：
4.9
作者：
Humphreys, G. S.;Merinopoulos, I.;Hallett, R. L.
通讯作者：
Hallett, R. L.
影响因子：
4.9
作者：
Asua, Victor;Vinden, Joanna;Rosenthal, Philip J.
通讯作者：
Rosenthal, Philip J.