tpo3 and dur3, Aspergillus fumigatus Plasma Membrane Regulators of Polyamines, Regulate Polyamine Homeostasis and Susceptibility to Itraconazole.
tpo3 and dur3, Aspergillus fumigatus Plasma Membrane Regulators of Polyamines, Regulate Polyamine Homeostasis and Susceptibility to Itraconazole.
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DOI：
10.3389/fmicb.2020.563139
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发表时间：
2020
影响因子：
5.2
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Chen M;Zhong G;Wang S;Zhu J;Tang L;Li L
烟曲霉菌是一种广为人知的条件致病菌，可引起侵袭性曲霉病(IA)感染，在免疫抑制人群中具有很高的死亡率。在临床治疗和农业生产中长期使用抗真菌药物唑会导致药效丧失或产生耐药性。耐药与细胞代谢产物及相应的基因转录有关。在本研究中，通过非靶向代谢组学和伊曲康唑(ITC)处理下的转录组学，我们确定了两个位于质膜上的多胺调节因子tpo3和du3，它们对烟曲霉的多胺稳态和对ITC的敏感性具有重要作用。在没有TPO3和/或DUT3的情况下，胞质多胺水平有一定程度的增加，从而增强了烟曲霉菌对ITC的耐受性。相比之下，tpo3或du3的过表达诱导了多胺的急剧增加，从而提高了烟曲霉菌对ITC的敏感性。进一步的分析表明，多胺通过清除中等浓度的ROS和促进高浓度的ROS的产生而不是调节药物的转运来影响烟曲霉菌对ITC的敏感性，这是浓度依赖性的。此外，抑制多胺的生物合成降低了细胞内的多胺含量，导致ROS的积累，并增强了ITC的抗真菌活性。有趣的是，伏立康唑(VOC)处理下的烟曲霉菌产生的ROS水平比ITC处理下的低得多。因此，我们的研究建立了多胺调节剂tpo3和du3、多胺动态平衡、ROS含量和ITC敏感性之间的联系。
Aspergillus fumigatus is a well-known opportunistic pathogen that causes invasive aspergillosis (IA) infections, which have high mortality rates in immunosuppressed individuals. Long-term antifungal drug azole use in clinical treatment and agriculture results in loss of efficacy or drug resistance. Drug resistance is related to cellular metabolites and the corresponding gene transcription. In this study, through untargeted metabolomics and transcriptomics under itraconazole (ITC) treatment, we identified two plasma membrane-localized polyamine regulators tpo3 and dur3, which were important for polyamine homeostasis and susceptibility to ITC in A. fumigatus. In the absence of tpo3 and/or dur3, the levels of cytoplasmic polyamines had a moderate increase, which enhanced the tolerance of A. fumigatus to ITC. In comparison, overexpression of tpo3 or dur3 induced a drastic increase in polyamines, which increased the sensitivity of A. fumigatus to ITC. Further analysis revealed that polyamines concentration-dependently affected the susceptibility of A. fumigatus to ITC by scavenging reactive oxygen species (ROS) at a moderate concentration and promoting the production of ROS at a high concentration rather than regulating drug transport. Moreover, inhibition of polyamine biosynthesis reduced the intracellular polyamine content, resulted in accumulation of ROS and enhanced the antifungal activity of ITC. Interestingly, A. fumigatus produces much lower levels of ROS under voriconazole (VOC) treatment than under ITC-treatment. Accordingly, our study established the link among the polyamine regulators tpo3 and dur3, polyamine homeostasis, ROS content, and ITC susceptibility in A. fumigatus.
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DOI：
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