Department of Biotechnology and Microbiology, Faculty of Sciences and Technology, University of Debrecen, Egyetem tér 1, Debrecen, H-4032, Hungary.
Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), 07745, Jena, Germany.
BMC Genomics. 2018 May 10;19(1):357. doi: 10.1186/s12864-018-4730-x.
Aspergillus fumigatus has to cope with a combination of several stress types while colonizing the human body. A functional interplay between these different stress responses can increase the chances of survival for this opportunistic human pathogen during the invasion of its host. In this study, we shed light on how the HO-induced oxidative stress response depends on the iron available to this filamentous fungus, using transcriptomic analysis, proteomic profiles, and growth assays.
The applied HO treatment, which induced only a negligible stress response in iron-replete cultures, deleteriously affected the fungus under iron deprivation. The majority of stress-induced changes in gene and protein expression was not predictable from data coming from individual stress exposure and was only characteristic for the combination of oxidative stress plus iron deprivation. Our experimental data suggest that the physiological effects of combined stresses and the survival of the fungus highly depend on fragile balances between economization of iron and production of essential iron-containing proteins. One observed strategy was the overproduction of iron-independent antioxidant proteins to combat oxidative stress during iron deprivation, e.g. the upregulation of superoxide dismutase Sod1, the thioredoxin reductase Trr1, and the thioredoxin orthologue Afu5g11320. On the other hand, oxidative stress induction overruled iron deprivation-mediated repression of several genes. In agreement with the gene expression data, growth studies underlined that in A. fumigatus iron deprivation aggravates oxidative stress susceptibility.
Our data demonstrate that studying stress responses under separate single stress conditions is not sufficient to understand how A. fumigatus adapts in a complex and hostile habitat like the human body. The combinatorial stress of iron depletion and hydrogen peroxide caused clear non-additive effects upon the stress response of A. fumigatus. Our data further supported the view that the ability of A. fumigatus to cause diseases in humans strongly depends on its fitness attributes and less on specific virulence factors. In summary, A. fumigatus is able to mount and coordinate complex and efficient responses to combined stresses like iron deprivation plus HO-induced oxidative stress, which are exploited by immune cells to kill fungal pathogens.
烟曲霉在定植人体时，必须应对多种类型的压力。这些不同应激反应之间的功能相互作用可以增加这种机会性病原体在入侵宿主时的生存机会。在这项研究中，我们通过转录组分析、蛋白质组谱和生长测定，阐明了 HO 诱导的氧化应激反应如何依赖于丝状真菌可用的铁。
在铁充足的培养物中，应用的 HO 处理仅引起可忽略的应激反应，但在缺铁时会对真菌造成有害影响。基因和蛋白质表达的大多数应激诱导变化不能从来自单个应激暴露的数据中预测，并且仅特征在于氧化应激加缺铁的组合。我们的实验数据表明，联合应激的生理效应和真菌的存活高度依赖于铁节约和必需含铁蛋白生产之间脆弱的平衡。观察到的策略之一是过度产生铁不依赖的抗氧化蛋白，以在缺铁时抵抗氧化应激，例如超氧化物歧化酶 Sod1、硫氧还蛋白还原酶 Trr1 和硫氧还蛋白同源物 Afu5g11320 的上调。另一方面，氧化应激诱导会推翻缺铁介导的几个基因的抑制。与基因表达数据一致，生长研究强调在 A. fumigatus 中，缺铁加剧了氧化应激易感性。
我们的数据表明，在单独的单一应激条件下研究应激反应不足以理解 A. fumigatus 如何适应人体等复杂和恶劣的栖息地。铁耗竭和 H2O2 的组合应激对 A. fumigatus 应激反应产生了明显的非加性效应。我们的数据进一步支持了这样的观点，即 A. fumigatus 在人类中引起疾病的能力强烈依赖于其适应性特征，而不是特定的毒力因子。总之，A. fumigatus 能够对缺铁加 HO 诱导的氧化应激等组合应激产生复杂而有效的反应，免疫细胞利用这些反应来杀死真菌病原体。
