Distinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection

Schrettl, Markus; Bignell, Elaine; Kragl, Claudia; Yasmin, Sabiha; Loss, Omar; Eisendle, Martin; Wallner, Anja; Arst, Herbert N.; Haynes, Ken; Haas, Hubertus

doi:10.1371/journal.ppat.0030128

Cited by 360 publications

(565 citation statements)

References 47 publications

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“…The fungal pathogen Aspergillus fumigatus produces four hydroxamate siderophores: fusarinine C and triacetylfusarinine C, which are secreted, and ferricrocin the intracellular iron storage siderophore in hyphae and hydroxyferricrocin the iron siderophore storage in conidial spores (Schrettl et al, 2007;Wallner et al, 2009;Haas, 2012). An additional siderophore-like molecule called hexadeydroastechrome was recently isolated from Aspergillus fumigatus and increased virulence when overexpressed in a murine model of infection (Yin et al, 2013).…”

Section: Siderophore-mediated Iron Acquisitionmentioning

confidence: 99%

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Tyrrell¹,

Callaghan²

2016

Microbiology

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Iron acquisition is vital to microbial survival and is implicated in the virulence of many of the pathogens that reside in the cystic fibrosis (CF) lung. The multifaceted nature of iron acquisition by both bacterial and fungal pathogens encompasses a range of conserved and speciesspecific mechanisms, including secretion of iron-binding siderophores, utilization of siderophores from other species, release of iron from host iron-binding proteins and haemoproteins, and ferrous iron uptake. Pathogens adapt and deploy specific systems depending on iron availability, bioavailability of the iron pool, stage of infection and presence of competing pathogens. Understanding the dynamics of pathogen iron acquisition has the potential to unveil new avenues for therapeutic intervention to treat both acute and chronic CF infections. Here, we examine the range of strategies utilized by the primary CF pathogens to acquire iron and discuss the different approaches to targeting iron acquisition systems as an antimicrobial strategy.

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Section: Siderophore-mediated Iron Acquisitionmentioning

confidence: 99%

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Tyrrell¹,

Callaghan²

2016

Microbiology

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“…To survive in the human host under conditions of iron starvation, A. fumigatus employs two high-affinity iron-uptake systems, reductive iron assimilation and the extracellular siderophores fusarinine C (FsC) and triacetylfusarinine C (TAFC), as well as the intracellular siderophore ferricrocin (FC) for iron storage and distribution [26,27]. To further characterize the role of riboflavin biosynthesis in iron utilization and siderophore production, wt and Δ riboB were analysed after growth in liquid minimal medium during iron starvation (-Fe), iron sufficiency (+Fe, 30 µM FeSO 4 ) and iron excess (hFe, 5 mM FeSO 4 ) supplemented with either a low (0.1 µM) or a high (2.5 µM) riboflavin concentration (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Riboflavin and pantothenic acid biosynthesis are crucial for iron homeostasis and virulence in the pathogenic mold Aspergillus fumigatus

et al. 2018

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Background: Aspergillus fumigatus is the most prevalent airborne fungal pathogen, causing invasive fungal infections mainly in immunosuppressed individuals. Death rates from invasive aspergillosis remain high because of limited treatment options and increasing antifungal resistance. The aim of this study was to identify key fungal-specific genes participating in vitamin B biosynthesis in A. fumigatus. Because these genes are absent in humans they can serve as possible novel targets for antifungal drug development. Methods: By sequence homology we identified, deleted and analysed four key A. fumigatus genes (riboB, panA, pyroA, thiB) involved respectively in the biosynthesis of riboflavin (vitamin B2), pantothenic acid (vitamin B5), pyridoxine (vitamin B6) and thiamine (vitamin B1). Results: Deletion of riboB, panA, pyroA or thiB resulted in respective vitamin auxotrophy. Lack of riboflavin and pantothenic acid biosynthesis perturbed many cellular processes including iron homeostasis. Virulence in murine pulmonary and systemic models of infection was severely attenuated following deletion of riboB and panA, strongly reduced after pyroA deletion and weakly attenuated after thiB deletion. Conclusions: This study reveals the biosynthetic pathways of the vitamins riboflavin and pantothenic acid as attractive targets for novel antifungal therapy. Moreover, the virulence studies with auxotrophic mutants serve to identify the availability of nutrients to pathogens in host niches.Abbreviations: BPS: bathophenanthrolinedisulfonate; BSA: bovine serum albumin; CFU: colony forming unit; -Fe: iron starvation; +Fe: iron sufficiency; hFe: high iron; NRPSs: nonribosomal peptide synthetases; PKSs: polyketide synthaseses; wt: wild type

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“…Likewise, fungi have developed mechanisms, such as siderophores, at the surface of their cell wall, which are high affinity chelators, helping to sequester metal ions from their host. Siderophores are essential for full virulence in fungi including Aspergillus fumigatus (Schrettl et al, 2007) and H. capsulatum (Hwang et al, 2008). Recently, C. albicans has been shown to adapt to metal-ion availability by exchanging cofactors of enzymes (Li et al, 2015).…”

Section: Amino Acids Ion Chelating/ion Sensingmentioning

confidence: 99%

Fungal sensing of host environment

Braunsdorf

Mailänder-Sánchez²,

Schaller

2016

Cellular Microbiology

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Summary To survive inside a host, fungi have to adapt to a changing and often hostile environment and therefore need the ability to recognize what is going on around them. To adapt to different host niches, they need to sense external conditions such as temperature, pH and to recognize specific host factors. The ability to respond to physiological changes inside the host, independent of being in a commensal, pathogenic or even symbiotic context, implicates mechanisms for sensing of specific host factors. Because the cell wall is constantly in contact with the surrounding, fungi express receptors on the surface of their cell wall, such as pheromone receptors, which have important roles, besides mediating chemotropism for mating. We are not restricting the discussion to the human host because the receptors and mechanisms used by different fungal species to sense their environment are often similar even for plant pathogens. Furthermore, the natural habitat of opportunistic pathogenic fungi with the potential to cause infection in a human host is in soil and on plants. While the hosts' mechanisms of sensing fungal pathogens have been addressed in the literature, the focus of this review is to fill the gap, giving an overview on fungal sensing of a host‐(ile) environment. Expanding our knowledge on host–fungal interactions is extremely important to prevent and treat diseases of pathogenic fungi, which are important issues in human health and agriculture but also to understand the delicate balance of fungal symbionts in our ecosystem.

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Distinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection

Cited by 360 publications

References 47 publications

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Riboflavin and pantothenic acid biosynthesis are crucial for iron homeostasis and virulence in the pathogenic mold Aspergillus fumigatus

Fungal sensing of host environment

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