Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1.
Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1.
复制标题
DOI：
10.1038/s41564-023-01377-z
复制
发表时间：
2023-07
影响因子：
28.3
通讯作者：
Anderson, Timothy J. C.
中科院分区：
文献类型：
--
作者：
Amambua-Ngwa, Alfred;Button-Simons, Katrina A. A.;Li, Xue;Kumar, Sudhir;Brenneman, Katelyn Vendrely;Ferrari, Marco;Checkley, Lisa A. A.;Haile, Meseret T. T.;Shoue, Douglas A. A.;McDew-White, Marina;Tindall, Sarah M. M.;Reyes, Ann;Delgado, Elizabeth;Dalhoff, Haley;Larbalestier, James K. K.;Amato, Roberto;Pearson, Richard D. D.;Taylor, Alexander B. B.;Nosten, Francois H.;D'Alessandro, Umberto;Kwiatkowski, Dominic;Cheeseman, Ian H. H.;Kappe, Stefan H. I.;Avery, Simon V. V.;Conway, David J. J.;Vaughan, Ashley M. M.;Ferdig, Michael T. T.;Anderson, Timothy J. C.
疟疾寄生虫在消化液泡中将宿主血红蛋白分解成多肽和氨基酸，输出到寄生虫细胞质中进行生长：中断这一过程是几种抗疟疾药物作用模式的核心。位于消化液泡膜上的氯喹（chloroquine， CQ）抗性转运蛋白pfcrt发生突变，赋予恶性疟原虫CQ抗性，并通常影响寄生虫的适应性。然而，其他寄生虫基因座在CQ抗性进化中的作用尚不清楚。在这里，我们使用群体基因组学，遗传杂交和基因编辑的组合来证明第二个液泡转运蛋白在抗性和代偿进化中都起着关键作用。冈比亚寄生虫的纵向基因组分析揭示了对假定的氨基酸转运体（pfaat1）变异S258L的选择的时间特征，该变异在1984年至2014年间与pfcrt1 K76T变异同时从0%增加到97%。寄生虫遗传杂交鉴定了CQ处理选择的含有pfaat1的6号染色体数量性状位点。基因编辑表明，pfaat1 S258L增强了CQ抗性，但代价是降低了适应度，而pfaat1 F313S（一种常见的东南亚多态性）降低了CQ抗性，同时恢复了适应度。我们的分析揭示了CQ抗性进化中隐藏的复杂性，表明pfaat1可能是抗性进化动力学的区域差异的基础，并通过操纵氨基酸和药物运输之间的平衡来调节寄生虫的抗性或适应性。利用群体基因组学、遗传杂交和基因编辑技术对恶性疟原虫氯喹耐药性进行了表征。
Malaria parasites break down host haemoglobin into peptides and amino acids in the digestive vacuole for export to the parasite cytoplasm for growth: interrupting this process is central to the mode of action of several antimalarial drugs. Mutations in the chloroquine (CQ) resistance transporter, pfcrt, located in the digestive vacuole membrane, confer CQ resistance in Plasmodium falciparum, and typically also affect parasite fitness. However, the role of other parasite loci in the evolution of CQ resistance is unclear. Here we use a combination of population genomics, genetic crosses and gene editing to demonstrate that a second vacuolar transporter plays a key role in both resistance and compensatory evolution. Longitudinal genomic analyses of the Gambian parasites revealed temporal signatures of selection on a putative amino acid transporter (pfaat1) variant S258L, which increased from 0% to 97% in frequency between 1984 and 2014 in parallel with the pfcrt1 K76T variant. Parasite genetic crosses then identified a chromosome 6 quantitative trait locus containing pfaat1 that is selected by CQ treatment. Gene editing demonstrated that pfaat1 S258L potentiates CQ resistance but at a cost of reduced fitness, while pfaat1 F313S, a common southeast Asian polymorphism, reduces CQ resistance while restoring fitness. Our analyses reveal hidden complexity in CQ resistance evolution, suggesting that pfaat1 may underlie regional differences in the dynamics of resistance evolution, and modulate parasite resistance or fitness by manipulating the balance between both amino acid and drug transport. Chloroquine resistance in Plasmodium falciparum is characterized using population genomics, genetic crosses and gene editing.
登录
查看更多内容
从冈比亚的颞和空间疟原虫对的基因组分析中选择的一致特征。
影响因子：
4.6
作者：
Amambua-Ngwa A;Jeffries D;Amato R;Worwui A;Karim M;Ceesay S;Nyang H;Nwakanma D;Okebe J;Kwiatkowski D;Conway DJ;D'Alessandro U
通讯作者：
D'Alessandro U
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
4.5
作者：
Henden, Lyndal;Lee, Stuart;Bahlo, Melanie
通讯作者：
Bahlo, Melanie
影响因子：
11.5
作者：
Ashley EA;Phyo AP
通讯作者：
Phyo AP
影响因子：
12.3
作者：
Cerqueira GC;Cheeseman IH;Schaffner SF;Nair S;McDew-White M;Phyo AP;Ashley EA;Melnikov A;Rogov P;Birren BW;Nosten F;Anderson TJC;Neafsey DE
通讯作者：
Neafsey DE