A key role for lipoic acid synthesis during Plasmodium liver stage development.
A key role for lipoic acid synthesis during Plasmodium liver stage development.
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DOI：
10.1111/cmi.12137
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发表时间：
2013-09
影响因子：
3.4
通讯作者：
Fidock D
中科院分区：
文献类型：
--
作者：
Falkard B;Kumar TR;Hecht LS;Matthews KA;Henrich PP;Gulati S;Lewis RE;Manary MJ;Winzeler EA;Sinnis P;Prigge ST;Heussler V;Deschermeier C;Fidock D
疟疾寄生虫在脊椎动物宿主和蚊子媒介之间交替的生命周期中成功导航，需要代谢产物合成和挽救途径的复杂相互作用。利用啮齿动物寄生虫伯氏疟原虫，我们探索了硫辛酸的合成和清除途径，硫辛酸是一种调节包括丙酮酸脱氢酶在内的α-酮酸脱氢酶活性的短链脂肪酸衍生物。在疟原虫中，硫辛酸要么在质外体中从头合成，要么从宿主清除到线粒体。我们的数据显示，缺乏顶体硫辛酸蛋白连接酶LipB的子孢子对小鼠的传染性显著减弱，体外研究证明，在肝内寄生虫成熟的最后阶段前不久，肝脏阶段非常晚期停滞。脂蛋白B缺乏的无性血液期寄生虫在正常的体外或体内条件下表现出不受损害的生长速度。然而，这些寄生虫在用硫辛酸类似物8-溴辛酸酯或降脂剂氯贝特处理后，在脂类限制的条件下生长减少。这一发现对了解首当其冲的疟疾首当其冲的营养不良儿童的疟疾发病机制具有重要意义。这项研究还强调了利用脂代谢途径设计基因减毒的子孢子疫苗的潜力。
The successful navigation of malaria parasites through their life cycle, which alternates between vertebrate hosts and mosquito vectors, requires a complex interplay of metabolite synthesis and salvage pathways. Using the rodent parasite Plasmodium berghei, we have explored the synthesis and scavenging pathways for lipoic acid, a short-chain fatty acid derivative that regulates the activity of α-ketoacid dehydrogenases including pyruvate dehydrogenase. In Plasmodium, lipoic acid is either synthesized de novo in the apicoplast or is scavenged from the host into the mitochondrion. Our data show that sporozoites lacking the apicoplast lipoic acid protein ligase LipB are markedly attenuated in their infectivity for mice, and in vitro studies document a very late liver stage arrest shortly before the final phase of intra-hepatic parasite maturation. LipB-deficient asexual blood stage parasites show unimpaired rates of growth in normal in vitro or in vivo conditions. However, these parasites showed reduced growth in lipid-restricted conditions induced by treatment with the lipoic acid analog 8-bromo-octanoate or with the lipid-reducing agent clofibrate. This finding has implications for understanding Plasmodium pathogenesis in malnourished children that bear the brunt of malarial disease. This study also highlights the potential of exploiting lipid metabolism pathways for the design of genetically attenuated sporozoite vaccines.
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影响因子：
30.3
作者：
Butler NS;Schmidt NW;Vaughan AM;Aly AS;Kappe SH;Harty JT
通讯作者：
Harty JT
影响因子：
17.1
作者：
Friesen, Johannes;Silvie, Olivier;Borrmann, Steffen
通讯作者：
Borrmann, Steffen
影响因子：
11.4
作者：
Crawford, Michael J.;Thomsen-Zieger, Nadine;Seeber, Frank
通讯作者：
Seeber, Frank
影响因子：
3.7
作者：
Angrisano, Fiona;Riglar, David T.;Baum, Jake
通讯作者：
Baum, Jake
影响因子：
4.7
作者：
Graewe, Stefanie;Retzlaff, Silke;Heussler, Volker T.
通讯作者：
Heussler, Volker T.