Plasmodium falciparum LipB mutants display altered redox and carbon metabolism in asexual stages and cannot complete sporogony in Anopheles mosquitoes.
Plasmodium falciparum LipB mutants display altered redox and carbon metabolism in asexual stages and cannot complete sporogony in Anopheles mosquitoes.
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DOI：
10.1016/j.ijpara.2020.10.011
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发表时间：
2021-05
影响因子：
4
通讯作者：
Sheiner L
中科院分区：
文献类型：
--
作者：
Biddau M;Santha Kumar TR;Henrich P;Laine LM;Blackburn GJ;Chokkathukalam A;Li T;Lee Sim K;King L;Hoffman SL;Barrett MP;Coombs GH;McFadden GI;Fidock DA;Müller S;Sheiner L
顶质体LipB缺失导致抗氧化剂表达的变化，这与加速分化有关。3D 7疟原虫在顶质体LipB缺失后表现出糖酵解和三羧酸循环活性的变化。当LipB从NF 54疟原虫中缺失时，所产生的寄生虫不能在蚊子中完成它们的发育。疟疾仍然是全球最重要的传染病之一。抗药性的出现和新的有效抗疟药物的短缺继续阻碍消灭疟疾议程。疟原虫对氧化还原环境的变化高度敏感。了解调节寄生虫氧化还原的机制有助于新药的设计。疟疾寄生虫具有复杂的氧化还原调节系统网络，该网络位于其胞质、胞体和质体（顶质体）中。虽然已经探索了硫氧还蛋白和谷胱甘肽途径的酶在寄生虫存活中的作用，但尚未测试顶质体中产生的α-硫辛酸（LA）的抗氧化作用。采取第一步在挑逗一个假定的作用，LA在氧化还原调节，我们分析了突变体恶性疟原虫（3D 7株）缺乏顶质体硫辛酸蛋白连接酶B（脂B）已知是耗尽的LA。我们的研究结果表明，在顶质体和细胞质中的氧化还原调节剂的表达的变化。我们进一步检测到寄生虫中心碳代谢的变化，lipB缺失导致糖酵解和三羧酸循环活性的变化。此外，在另一种疟原虫细胞系（NF 54）中，lipB的缺失影响了蚊子的发育，阻止了感染性子孢子阶段的检测。虽然目前尚不清楚所观察到的表型是否相关，但这些发现标志着LA生物合成是在无性阶段氧化还原调节背景下进一步研究的重要课题，并指出LipB是开发新传播药物的潜在靶点。
Apicoplast LipB deletion leads to changed antioxidant expression that precedes and coincides with accelerated differentiation. 3D7 Plasmodium exhibits changes in glycolysis and tricarboxylic acid cycle activity after deletion of apicoplast LipB. When LipB is deleted from NF54 Plasmodium, the resulting parasites cannot complete their development in mosquitoes. Malaria is still one of the most important global infectious diseases. Emergence of drug resistance and a shortage of new efficient antimalarials continue to hamper a malaria eradication agenda. Malaria parasites are highly sensitive to changes in the redox environment. Understanding the mechanisms regulating parasite redox could contribute to the design of new drugs. Malaria parasites have a complex network of redox regulatory systems housed in their cytosol, in their mitochondrion and in their plastid (apicoplast). While the roles of enzymes of the thioredoxin and glutathione pathways in parasite survival have been explored, the antioxidant role of α-lipoic acid (LA) produced in the apicoplast has not been tested. To take a first step in teasing a putative role of LA in redox regulation, we analysed a mutant Plasmodium falciparum (3D7 strain) lacking the apicoplast lipoic acid protein ligase B (lipB) known to be depleted of LA. Our results showed a change in expression of redox regulators in the apicoplast and the cytosol. We further detected a change in parasite central carbon metabolism, with lipB deletion resulting in changes to glycolysis and tricarboxylic acid cycle activity. Further, in another Plasmodium cell line (NF54), deletion of lipB impacted development in the mosquito, preventing the detection of infectious sporozoite stages. While it is not clear at this point if the observed phenotypes are linked, these findings flag LA biosynthesis as an important subject for further study in the context of redox regulation in asexual stages, and point to LipB as a potential target for the development of new transmission drugs.
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