Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition.
Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition.
复制标题
DOI：
10.1371/journal.ppat.1009734
复制
发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Morrison LJ
中科院分区：
文献类型：
--
作者：
Steketee PC;Dickie EA;Iremonger J;Crouch K;Paxton E;Jayaraman S;Alfituri OA;Awuah-Mensah G;Ritchie R;Schnaufer A;Rowan T;de Koning HP;Gadelha C;Wickstead B;Barrett MP;Morrison LJ
动物非洲锥虫病（AAT）是一种在撒哈拉以南非洲流行的使人衰弱的牲畜疾病，其主要原因是原生动物寄生虫刚果锥虫。与已被广泛研究的T. brucei，关于T.刚果语。在这里，我们使用组学技术和新的遗传工具相结合，以了解T。congolensea感染的血吸虫，并测试是否代谢差异相比，T。布鲁氏菌对代谢抑制敏感性的影响。就像T. brucei，糖酵解在T.刚果能量代谢然而，血流阶段T的葡萄糖吸收率显着较低。在低至2 mM的浓度下培养时，细胞保持活力。代替丙酮酸，主要的糖酵解终点是琥珀酸、苹果酸和乙酸。转录组学分析显示，在T. congolense，与T.布鲁塞。葡萄糖的稳定同位素标记使得T。brucei和T.刚果，突出核苷酸和饱和脂肪酸代谢的差异。为了验证代谢的相似性和差异，两个物种都用代谢抑制剂处理，证实电子传递链活性在T.刚果语。然而，与T.布鲁塞。令人惊讶的是，T。刚果金木霉对脂肪酸合成抑制剂表现出显著的抗性，包括对脂肪酶和脂肪酸合成酶抑制剂奥利司他的EC 50比木霉高780倍。布鲁塞。这些数据突出表明，血流形成T。congolense与T.布氏杆菌在代谢的关键领域，具有介于血流阶段和昆虫阶段之间的几个特征。布鲁塞。这些结果对药物开发、耐药机制和宿主-病原体相互作用具有重要意义。动物非洲锥虫病（AAT），也称为Nagana，是一种影响撒哈拉以南非洲牲畜的毁灭性疾病。AAT主要由寄生虫刚果锥虫引起，但我们对这种病原体的生物学知识很少，特别是与相关物种T。布鲁氏杆菌，其亚种引起人类疾病昏睡病。了解T.为了深入了解这种重要病原体的感染生物学，以及提供确定新药物靶点的潜力，刚果人至关重要。在这项工作中，我们解决了缺乏知识的T。对刚果红T. congolense的核心代谢进行了综合分析，并与T.布鲁塞。然后，我们使用代谢差异的发现来预测对代谢功能抑制剂的差异敏感性。我们表明，不像T。布鲁氏菌，其中葡萄糖代谢导致高水平的丙酮酸排泄，T. Congolense将葡萄糖代谢成其它终产物，即琥珀酸、苹果酸和乙酸。此外，T. congolense使用葡萄糖来补充代谢的其他区域。进一步的分析表明T.刚果人主要清除脂质和脂肪酸，而不是重新合成它们。为了验证这些发现，我们确认T。与T. brucei，特别是T.刚果人对脂肪酸合成抑制剂的敏感性显著降低。本研究为进一步了解T. congolense，深入了解这种寄生虫与T.布鲁塞。
Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense. In comparison to the well-studied T. brucei, there is a major paucity of knowledge regarding the biology of T. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites, and test whether metabolic differences compared to T. brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T. brucei, glycolysis plays a major part in T. congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T. congolense, with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T. congolense, compared to T. brucei. Stable-isotope labelling of glucose enabled the comparison of carbon usage between T. brucei and T. congolense, highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T. congolense. However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T. brucei. Strikingly, T. congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC50 for the lipase and fatty acid synthase inhibitor Orlistat, compared to T. brucei. These data highlight that bloodstream form T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions. Animal African Trypanosomiasis (AAT), also known as Nagana, is a devastating disease affecting livestock across sub-Saharan Africa. AAT is primarily caused by the parasite Trypanosoma congolense, yet our biological knowledge about this pathogen is poor, especially compared to the related species T. brucei, subspecies of which cause the human disease Sleeping Sickness. Understanding the core metabolism of T. congolense is crucial in order to gain insights into the infection biology of this important pathogen, as well as providing the potential to identify new drug targets. In this work, we addressed the lack of knowledge concerning T. congolense by carrying out a comprehensive analysis of core metabolism, and comparing the data to T. brucei. We then used the findings of metabolic differences to predict differential sensitivity to inhibitors of metabolic function. We show that unlike T. brucei, where glucose metabolism leads to high levels of pyruvate excretion, T. congolense metabolises glucose to other end-products, namely succinate, malate and acetate. Moreover, there are pronounced differences in the way T. congolense uses glucose to feed into other areas of metabolism. Further analysis also suggests that T. congolense mostly scavenges lipids and fatty acids, rather than synthesising them de novo. To validate these findings, we confirm that T. congolense is differentially susceptible to metabolic inhibitors compared to T. brucei, and that, in particular, T. congolense is significantly less sensitive to inhibitors of fatty acid synthesis. Our study provides a foundation of functional metabolic knowledge on T. congolense, with insights into how this parasite fundamentally differs from T. brucei.
登录
查看更多内容
影响因子：
3.3
作者：
Abbas AH;Silva Pereira S;D'Archivio S;Wickstead B;Morrison LJ;Hall N;Hertz-Fowler C;Darby AC;Jackson AP
通讯作者：
Jackson AP
影响因子：
4.8
作者：
Bochud-Allemann, N;Schneider, A
通讯作者：
Schneider, A
DOI：
10.1016/j.biocel.2017.01.015
发表时间：
2017-04-01
影响因子：
4
作者：
Allmann, Stefan;Bringaud, Frederic
通讯作者：
Bringaud, Frederic
影响因子：
2.1
作者：
BIENEN, EJ;WEBSTER, P;FISH, WR
通讯作者：
FISH, WR
影响因子：
2.1
作者：
AGOSIN, M;VONBRAND, T
通讯作者：
VONBRAND, T