Identification of ferrichrome- and ferrioxamine B-mediated iron uptake by <i>Aspergillus fumigatus</i>

Park, Yong Sung; Kim, Ju Yeon; Yun, Cheol Won

doi:10.1042/bcj20160066

Cited by 25 publications

(21 citation statements)

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“…The significance of the low affinity iron transport has not been studied in details so far [ 29 , 30 ]. Both RIA and siderophore-mediated iron uptake are important in adaptation to iron starvation, however, only the contribution of siderophore biosynthesis and ferri-siderophore transport to virulence has been demonstrated until now [ 30 , 32 – 34 ]. The transcription factor HapX is crucial in regulating the iron starvation stress response in A. fumigatus [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…No specific phenotype was observed for A. fumigatus Δ sit2 , however it has recently been shown that Sit2 is involved in ferrioxamine B uptake (Park et al, 2016). ImpC (AFUA_3G03670) is a putative ABC transporter and mRNA expression of ImpC is induced in response to iron-deplete conditions (Kragl et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Functional Investigation of Iron-Responsive Microsomal Proteins, including MirC, in Aspergillus fumigatus

et al. 2017

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The functionality of many microsome-associated proteins which exhibit altered abundance in response to iron limitation in Aspergillus fumigatus is unknown. Here, we generate and characterize eight gene deletion strains, and of most significance reveal that MirC (AFUA_2G05730) contributes to the maintenance of intracellular siderophore [ferricrocin (FC)] levels, augments conidiation, confers protection against oxidative stress, exhibits an intracellular localization and contributes to fungal virulence in the Galleria mellonella animal model system. FC levels were unaffected following deletion of all other genes encoding microsome-associated proteins. MirC does not appear to play a role in either siderophore export from, or uptake into, A. fumigatus. Label-free quantitative proteomic analysis unexpectedly revealed increased abundance of siderophore biosynthetic enzymes. In addition, increased expression of hapX (7.2 and 13.8-fold at 48 and 72 h, respectively; p < 0.001) was observed in ΔmirC compared to wild-type under iron-replete conditions by qRT-PCR. This was complemented by significantly elevated extracellular triacetylfusarinine C (TAFC; p < 0.01) and fusarinine C (FSC; p < 0.05) siderophore secretion. We conclude that MirC plays an important role in FC biosynthesis and contributes to the maintenance of iron homeostasis in A. fumigatus.

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“…In A. fumigatus, the SIDA gene that encodes the L-ornithine-N-monooxygenase is essential for siderophore production and contributes to virulence [75,147,152]. A. fumigatus also possess a highly conserved orthologs of the S. cerevisiae SIT1 and SIT2 transporter genes, and it was demonstrated that these transporters play a role in the uptake of ferrioxamine B and ferrichrome [153]. The deletion of the SID1 gene (ortholog of SIDA) in H. capsulatum, abolishes the siderophore biosynthesis pathway and inhibits fungal growth in bone marrow-derived macrophages and in mice.…”

Section: Siderophore Uptakementioning

confidence: 99%

Iron Assimilation during Emerging Infections Caused by Opportunistic Fungi with emphasis on Mucorales and the Development of Antifungal Resistance

Stanford

Voigt

2020

Genes

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Iron is a key transition metal required by most microorganisms and is prominently utilised in the transfer of electrons during metabolic reactions. The acquisition of iron is essential and becomes a crucial pathogenic event for opportunistic fungi. Iron is not readily available in the natural environment as it exists in its insoluble ferric form, i.e., in oxides and hydroxides. During infection, the host iron is bound to proteins such as transferrin, ferritin, and haemoglobin. As such, access to iron is one of the major hurdles that fungal pathogens must overcome in an immunocompromised host. Thus, these opportunistic fungi utilise three major iron acquisition systems to overcome this limiting factor for growth and proliferation. To date, numerous iron acquisition pathways have been fully characterised, with key components of these systems having major roles in virulence. Most recently, proteins involved in these pathways have been linked to the development of antifungal resistance. Here, we provide a detailed review of our current knowledge of iron acquisition in opportunistic fungi, and the role iron may have on the development of resistance to antifungals with emphasis on species of the fungal basal lineage order Mucorales, the causative agents of mucormycosis.

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Identification of ferrichrome- and ferrioxamine B-mediated iron uptake by Aspergillus fumigatus

Cited by 25 publications

References 41 publications

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

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

Functional Investigation of Iron-Responsive Microsomal Proteins, including MirC, in Aspergillus fumigatus

Iron Assimilation during Emerging Infections Caused by Opportunistic Fungi with emphasis on Mucorales and the Development of Antifungal Resistance

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