Additional oxidative stress reroutes the global response of Aspergillus fumigatus to iron depletion

Abstract

BackgroundAspergillus 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 H2O2-induced oxidative stress response depends on the iron available to this filamentous fungus, using transcriptomic analysis, proteomic profiles, and growth assays.ResultsThe applied H2O2 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.ConclusionsOur 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 H2O2-induced oxidative stress, which are exploited by immune cells to kill fungal pathogens.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4730-x) contains supplementary material, which is available to authorized users.

Novel intermicrobial molecular interaction: Pseudomonas aeruginosa Quinolone Signal (PQS) modulates Aspergillus fumigatus response to iron

“…However, in contrast to normoxic conditions, under hypoxic conditions titrations of additional iron alone decreased Af metabolism slightly, and significantly at higher Fe concentrations (). This suggested Fe adversely effects an oxidative stress [25, 50, 51] of Af, under hypoxic conditions. This finding was confirmed in a third experiment, comparing normoxic and hypoxic conditions concurrently, over a range 0.1–1000 µM Fe, and normoxic boosting by Fe, along with hypoxic depression by Fe, was seen at all concentrations.…”

Genome-Wide Association for Itraconazole Sensitivity in Non-Resistant Clinical Isolates ofAspergillus fumigatus

“…To investigate the expression patterns of our candidate genes Afu2g02220 and Afu2g02140, we obtained FPKM values as well as fold-change and p-values for pairwise comparisons from FungiDB (https://fungidb.org/fungidb/) (48) for oxidative stress, iron depletion, growth in blood and minimal media, and ITCZ exposure (49,50).…”

Cross kingdom analysis of putative quadruplex-forming sequences in fungal genomes: novel antifungal targets to ameliorate fungal pathogenicity?

“…Upregulated genes in germinating conidia and hyphae [39], during hypoxia [40], and during iron limitation or oxidative stress [41] were identified using publicly available transcriptome datasets. These were analysed in FungiDB (https://fungidb.org/) [42].…”

“…Although PQS could be found in important fungal genes, we aimed to link the presence of PQS within these organisms with potential biological and pathophysiological functions. To investigate this, transcriptome datasets of A. fumigatus during germination [39], hypoxia [40], iron limitation and oxidative stress [41], or in biofilms [43] were analysed. In each instance, the top 20 upregulated genes (compared to dormant/unstressed A. fumigatus controls) were investigated for the presence and frequency of PQS.…”