The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite.
The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite.
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顶质体与疟疾寄生虫的发热存活和青蒿素耐药性有关。
DOI：
10.1038/s41467-021-24814-1
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发表时间：
2021-07-27
影响因子：
16.6
通讯作者：
Adams JH
中科院分区：
文献类型：
--
作者：
Zhang M;Wang C;Oberstaller J;Thomas P;Otto TD;Casandra D;Boyapalle S;Adapa SR;Xu S;Button-Simons K;Mayho M;Rayner JC;Ferdig MT;Jiang RHY;Adams JH
对一线抗疟复方青蒿素疗法具有耐药性的恶性疟原虫的出现和传播有可能抹杀过去十年在防治疟疾方面取得的可观成果。在这里，我们建立了一个大规模的表型筛选管道，并利用它对恶性疟原虫进行大规模的前向遗传表型筛选，以确定允许寄生虫在发热温度下存活的基因。筛选确定超过200种恶性疟原虫突变体对温度升高的不同反应。这些突变体更可能对青蒿素衍生物以及氧化应激加剧敏感。恶性疟原虫对发热温度和青蒿素耐受的关键过程包括与蛋白质折叠、热休克和蛋白酶体介导的降解相关的高度必需的、保守的途径，以及意想不到的类异戊二烯生物合成，这源于寄生虫藻类内生质体的祖先基因组，即顶质体。顶质体靶基因通常在热休克反应中上调，其他在植物和藻类基因组中具有同源物的疟原虫基因也是如此。恶性疟原虫似乎利用其先天发热反应机制介导对青蒿素的耐药性。这两种反应都依赖于寄生虫基因组中的内共生体衍生基因，这表明疟原虫的进化起源与自由生活的祖先有关。反复发烧是疟疾的标志。在此，对引起疟疾的恶性疟原虫进行了大规模的前向遗传筛选，确定了与寄生虫对宿主发热耐受相关的基因，包括顶质体靶向类异戊二烯生物合成与青蒿素耐药性共享的特征。
The emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry out a large-scale forward-genetic phenotype screen in P. falciparum to identify genes allowing parasites to survive febrile temperatures. Screening identifies more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants are more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin include highly essential, conserved pathways associated with protein-folding, heat shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general are upregulated in response to heat shock, as are other Plasmodium genes with orthologs in plant and algal genomes. Plasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiont-derived genes in the parasite’s genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors. Repeating fever is a hallmark of malaria. Here, a large-scale forward genetic screen in malaria-causing Plasmodium falciparum identifies genes associated with parasite tolerance to host fever, including apicoplast targeted isoprenoid biosynthesis—sharing features with artemisinin resistance.
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影响因子：
5.2
作者：
Imlay, Leah;Odom, Audrey R
通讯作者：
Odom, Audrey R
影响因子：
4.4
作者：
Gibbons J;Button-Simons KA;Adapa SR;Li S;Pietsch M;Zhang M;Liao X;Adams JH;Ferdig MT;Jiang RHY
通讯作者：
Jiang RHY
影响因子：
7
作者：
Gisselberg, Jolyn E.;Zhang, Lichao;Yeh, Ellen
通讯作者：
Yeh, Ellen
影响因子：
4.8
作者：
Estévez, JM;Cantero, A;León, P
通讯作者：
León, P
影响因子：
6.7
作者：
Gnadig, Nina F.;Stokes, Barbara H.;Fidock, David A.
通讯作者：
Fidock, David A.