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.

Highlights

  • Aspergillus fumigatus has to cope with a combination of several stress types while colonizing the human body

  • Comparison of transcriptomic and proteomic data In order to test how iron deprivation modifies the oxidative stress response of A. fumigatus, the transcriptome (Fig. 1, Table 1) and proteome of four different cultures, -Fe/-H2O2, +Fe/+H2O2) (H2O2-treated), -Fe/+H2O2, and + Fe/H2O2 cultures were studied in three biological replicates

  • The -Fe/-H2O2 and the -Fe/+H2O2 conditions resulted in significant changes at both the transcriptome and the proteome level in comparison to +Fe/-H2O2 control cultures (Fig. 2, Tables 2 and 3)

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Summary

Introduction

Aspergillus fumigatus has to cope with a combination of several stress types while colonizing the human body. Aspergillus fumigatus is a ubiquitous fungal species, which occurs commonly on decaying organic matter and in soil under a wide variety of conditions [1, 2] This mould is known as one of the most important airborne human pathogenic fungi with an outstandingly high mortality rate (50–95%) in immunocompromised patients, who suffer from an invasive A. fumigatus infection (referred to as invasive aspergillosis) [3,4,5,6]. The significance of the low affinity iron transport has not been studied in details so far [29, 30] Both RIA and siderophoremediated iron uptake are important in adaptation to iron starvation, only the contribution of siderophore biosynthesis and ferri-siderophore transport to virulence has been demonstrated until now [30, 32,33,34]. It down-regulates iron-consuming pathways such as ironsulfur cluster assembly, heme biosynthesis, respiration, the tricarboxylic-acid (TCA) cycle and amino acid metabolism, while it up-regulates iron acquisition via siderophore biosynthesis [35]

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