Key findings:

Siderophores, including Fusarinines C (FsC) and Triacetylfusarinine C (TAFC), play a crucial role in Aspergillus fumigatus's virulence by regulating iron acquisition and distribution. Orthinine hydroxylation is key in siderophore biosynthesis. Iron metabolism in A. fumigatus involves GATA (SreA) and bZip (HapX) transcription factors, srbA, and ergosterol biosynthesis, crucial for growth under varying iron conditions.

What is known and what is new?

Siderophores are known iron-chelating compounds secreted by microorganisms to regulate iron acquisition and storage. Aspergillus fumigatus, a fungal pathogen, produces siderophores like Fusarinines C (FsC) and Triacetylfusarinine C (TAFC) for iron uptake and storage, crucial for its virulence. This study adds to this knowledge by highlighting the significance of orthinine hydroxylation in siderophore biosynthesis in A. fumigatus. It also identifies key transcription factors (GATA/SreA, bZip/HapX), srbA, and ergosterol biosynthesis in regulating iron metabolism in A. fumigatus, crucial for growth under varying iron conditions. 

What is the implication, and what should change now?

The implications of this study are significant for understanding how A. fumigatus regulates iron metabolism, which is crucial for its virulence. This knowledge could lead to the development of new strategies for combating A. fumigatus infections, such as targeting key iron metabolism pathways. Additionally, the study underscores the importance of considering the complex mechanisms involved in iron regulation in fungi, which could have broader implications for understanding fungal pathogenesis and developing antifungal therapies.

Aspergillus fumigatus an omnipotent saprophytic fungus resides mainly in decaying organic matter or in soil and behaves as a recycler in nature. This belongs to a flexible metabolism under the environmental conditions which meets its nutritional requirements (Kwon-Chung et al., 2013) [1] and is isolated from human habitats (Hirsch et al., 2000) [2] and vegetable compost heaps (Beffa et al., 1998 and Ryckeboer et al., 2003) [3,4]. 

Now-a-days, A. fumigatus is considered as a weak pathogen causing allergic diseases, observed among individuals like farmers lung exposed to aspergilloma or conidia (Dixon et al., 1992; Kwon Chung et al., 1992 [5,6] and Pennington., 1988) [7]. It causes many disorders effecting human organs like immune system, immune compromised hosts, lungs, liver, brain and central nervous system. These disorders may cause many diseases in humans such as asthma, sinusitis, ethimoid sinuses, subsequent cranial bone osteomylitis, intracranial extension, episoidic wheezing, pulmonary infiltrates, sputum and blood eosinophilia, ABA, asperigillosis, Leukemia, cystic fibrosis, and tuberculosis (Table 1).

Table 1: Diseases Caused By A. Fumigates Affecting Different Human Organs

                A. Fumigatus can grow in 80% of human serum media, this is essential and possess an efficient mechanism for acquiring of iron [18].        

 Pulmonary disease is represented by conidial germination in the spore inhalation and human lungs. During spore germination, three crucial steps are distinguished they are as follows:

(i). At environmental conditions, activation of resting spore

(ii). isotropic growth that is responsible in growth of the wall and uptake of water 

(iii).The new mycelium originates from the germ tube formation, as this is involved in the polarized growth (d’ Enfert., 1997 and Momany., 2002) [19].

cell wall of A. fumigatus  is composed of a fibrillar branched β1,3-glucan core bound to chitin, galactomannan and β1,3-1,4-glucan, embedded in an amorphous cement composed of α1,3-glucan, galactomannan and polygalactosamine [20]. Hyphal cell wall is crucial to host cell resistance and for penetration of solid nutrient substrates by A. fumigatus. Homologues of the yeast PIR proteins face scantiness by A. fumigatus, which are credibly bound to β1,3-glucans by an alkali-labile bond [20]. This genome consists of 26 type of clusters with non-ribosomal peptide synthase, polyketide synthase with and/or without dimethylallyl tryptophan synthase genes [21]. 

In animals, A. fumigatus causes aspergillosis in serum, neutropenic, urinary excretion, was observed in guinea pigs, mice and rabbit (Table 2). The detection methods for the 

Infected fumigatus are in urine via immunoassays in guinea pigs, from fumigatus strain (90906) in mice, antigen in urine and serum by counter immune electrophoresis in rabbit.

Table 2: Disease Occurrence with Infected A. Fumigatus in Animals and Its Detection Methods

A. Fumigatus is considered as air borne fungal pathogen of humans, (Tekaia et al., 2005) [25] and a role of genome sequence. Recently A. Fumigatus is considered as one of the best studied fungal filamentous species. This genome sequence permit molecular analysis and allows “genome mining” (Nierman et al., 2005) [26].  However, A. fumigatus lacks particular uptake systems for iron host sources as transferrin heme and/ or ferritin (Schrettl et al., 2004) [27].

2. Requirement Iron by A. Fumigatus:

For all prokaryotes nearly and to all eukaryotes, iron is an essential nutrient [28]. In Earth’s crust, it is the fourth most opulent transition element [29] that can present in two oxidation states, they are as: Fe (II) Fe (III). The general functions of metabolic and cellular process for the requirement of iron occurs at, electron transport chain, tricarboxylic acid cycle amino acid metabolism andoxidative phosphorylation in A. fumigatus. Iron helps in nucleic acid synthesis and biosynthesis of vitamins, porphyrins, toxins, cytochromes, pigments, aromatic compounds, siderophores, and antibiotics (Table 3).

At physiological pH level (7.35–7.40), the ferric form of iron Fe (III) is insoluble and ferrous form of iron Fe (II) is soluble [30]. The variable valence of the iron allows it to act as a major role in the oxidation reduction reactions [31]. Iron at excess conditions catalyzes the formation of ROS that can damage cellular components (Table 3), on the other hand hydrophobicity of microbial surface reduces, which changes the surface protein composition and leads to the formation of biofilm at low conditions. There are some mechanisms for balancing storage, consumption and acquisition of iron in order to overcome limitation and excess amounts of iron (Table 3).

Table 3: Requirement of Iron in A. fumigatus

3. Siderophores Production by A. fumigatus:

Mono and/or di iron are assimilated into heme sulfur clusters, as this metal is an obligatory co-factor for biosynthesis of DNA, cellular process and sterols varieties [34]. The limitation of iron availability increases in atmospheric oxygen which is owed to its oxidation into the insoluble ferric hydroxides [38]. Microorganisms have developed few particular strategies like siderophore production, because of the limited availability of iron in the environment [39].

Siderophores (In Greek, sideros means “iron” and phores means “bearer”) are the metal chelating compounds that functions mainly to encapsulate the insoluble ferric iron from environment [40].

Classification of hydroxamate siderophores in A.Fumigatus:

A. Fumigatus produce hydroxamate group of siderophores. Siderophores of Biosynthesis in A. Fumigatus is by ornithine hydroxylation (orn) catalysed by the ornithine monooxygenase Sid A. For siderophore biosynthesis 40-phosphopantetheinyl transferase PptA is crucial because lysine-biosynthetic a-aminoadipate reductase, NRPS along with polyketide synthetases involves activation through this enzyme [41,42]. 

In A. Fumigatus, 4 types of siderophores are secreted (Table 5). Two in extracellular namely fusarinines C (Fs C) and triacetylfusarinineC (TAFC). Two in intracellular namely hyphal ferricrocin (FC) and hydroxyferricrocin (HFC)

In FsC R =H, all siderophores were represented in ferric forms, except rhodotorulic acid., and Fe (III), ester bonds and peptide bonds were displayed in blue, green and  red colours respectively in Table 4.

Table 4: Chemical compounds and structures of four types of siderophores produced by A. fumigatus

4.  Siderphore biosynthesis in A. fumigatus:

Ornithine monooxygenase SidA which catalyses the hydroxylation of ornithine is the prior catalytic step in all four types of siderophore biosynthesis. The splitting of different aceyl groups that transfers to N⁵-hydroxyornithine [41,42]. In mitochondrion, the first essential precursor ornithine is produced and all its biosynthetic pathway export through the transporter AmcA to the cytosolis were upregulated transcriptionally under iron deprivation in [46].

Conversion of arginine to ornithine by the arginase AgaA in response to iron starvation is converted in the cytosol, as ornithine is a precursor of arginine. SidF transfers, the transacylase anhydromevalonyl to N⁵-hydroxy-L-ornithine in the extracellular siderophores represented in (Fig 2) [47]. Two transacetylases like SidL and an unknown enzyme are required for the intracellular ferrichrome type of siderophores for their upregulation by starvation of iron [48]. 

Fusarinines and ferrichromes are formed primarily by Sid D and Sid C, two different non ribosomal peptide synthetases (NRPSs), an enzyme which is best recognized from secondary metabolism in A. fumigatus [47]. “GCN5-related N-acetyltransferases (GNAT)” proteins comes under SidF and SidL. lysine-biosynthesis involves in Polyketide synthetases similar to NRPSs, and the a-aminoadipate reductase, this depends on Sfp-type 40-phosphopantetheinyl transferase activation, entitled as PptA [42].   

Similar to fusarinine, biosynthesis of ferrichrome A is also connected to biosynthesis of isoprenoide as methylglutaconyl-CoA which is derived from HMG-CoA through the enoyl-CoA-hydratase Fer4 dehydration [49]. As for TAFC biosynthesis mevalonate acts as a precursor and produces HMG-CoA reductase Hmg1. Additionally, the over expression of mevalonate increases production of TAFC. The inhibition of lovastin mediated Hmg 1 blocks biosynthesis of TAFC. At isoprenoid biosynthetic pathway, mevalonate acts as an intermediate with ergosterol as significant product, this pathway is helpful in acting against fungal diseases, as it increase resistance in amphotericin B and azoles. Whereas, iron deficiency reduces the level of cellular ergosterol due to the iron requirement for biosynthesis of ergosterol [50].

SidG is important for the TAFC biosynthesis. This deficiency of sidG, removes production of TAFC with increase in the production of FsC, and neither affects virulence nor growth [47] ∆sidI, sidH, sidF, sidD (Extracellular) and ∆sid C mutants (Intracellular) causes partial attenuation of virulence (Table 5).

With the only hydroxylation, HFC is derived from FC which is catalyzed by an unknown gene product shown in (Fig 2) (Schrettl et al., 2007) [47]. Both the extra and intra cellular siderophores are important for virulence, because the entire SB (ΔsidA mutant) elimination causes in supreme avirulence of invasive pulmonary aspergillosis in a murine model of A. fumigatus (Table 5) [51, 52].

Fig 2:Siderphore Biosynthesis Pathway in A. fumigatus indicates in blue color and it is attached to the isoprenoide biosynthesis and also ornithine and/ or arginine metabolism. Enzymes involved are described briefly in the text box. During iron starvation, enzymatic steps upregulated transcriptionally and marked by red arrows. A broken arrow displays reactions involving enzymes more than one. Peroxisome and mitochondrion are shaded in grey and yellow, respectively [53].

Table 5: Siderophores produced by A. fumigatus

5. Iron homeostasis in A.fumigatus:

Iron homeostasis inculpate the two central transcription factors (TF) they are       (i) GATA factor- SreA and (ii) bZip factor- HapX (Haas et al., 1999; Hortschansky et al., 2007; Schrettl et al., 2008, 2010 a) [57-60]. During iron sufficiency, SreA presume by bioinformatic analyses to identify ATCWGATAA sequences, in order to represses iron toxicity, high affinity iron uptake, including reductive iron assimilation and the siderophore system [59]. During iron deficiency, HapX decreases iron consuming pathways such as respiration, heme biosynthesis, tricarboxylic cycle and ribosome biogenesis to reserve iron shown in   (Table 6).

 Moreover, siderophores and ribotoxin AspF1 synthesis is activated by HapX and furtherly by coordination of siderophore biosynthesis with the supply of ornithine as its precursor in A. fumigatus. There is an interconnection loop between the two central transcriptional factors (SreA) and (HapX). During iron deficiency HapX repress sreA and while during iron sufficiency SreA represses hapX, where as both factors are regulated by iron blocking HapX function and activation of SreA function post translationally. On inactivation of either SreA or HapX factors, the malignant effects are cramped growth during sufficiency and/ or deficiency with their mode of action and expression pattern is shown in (Fig 3) respectively.

A. fumigates consists of 24 genes which are having functional and identical characterization increases in iron that tends to cause respiration and tri carboxylic acid cycle as iron dependent [61]. Analysis of Proteome by A. fumigatus reveals that with increasing the contents of heme, cellular iron, zinc and copper, increases the protein production in tricarboxylic acid cycle, glycolysis and respiration in hypoxia [62].

 SrbA regulates iron uptake in response to adaptation of hypoxia and in most eukaryotes it is sustained and activates siderophore and transcriptional factor of sterol regulatory element binding protein “(SREBP)” [61]. To maintain sterol homeostasis, cellular sterol exhaustion activates these TFs (Bien and Espenshade., et al., 2010); (Blatzer et al., 2011 a) [63, 64]. Deficiency of SrbA decreases the content of cellular ergosterol, resistance against azole drugs and hypoxic growth is arrested as well as virulence [61].

During iron starvation, SrbA transcriptional activation is independent of SreA and HapX factors. So, this states that A. fumigatus recognizes iron not only through the HapX and  SreA but also through SrbA and sterol biosynthesis. Whereas deficiency of SreA leads to the excessive uptake of iron and upregulates both the enzymes transcriptionally [65]. The shortage in SreA or HapX both the factors leads to reddish hyphal pigmentation caused by metabolic deregulation. Only deficiency in HapX of bZip factor occurs A. fumigatus virulence of aspergillosis in murine models [59,60], which draws attention in the limitation stages of iron adaptation role (Table 6). 

In order to maintain cell wall integrity, secondary metabolism, protection against reactive oxygen species and mitogen activated protein kinase (MAPK), iron starvation triggers nuclear localization and phosphorylation in A. fumigatus whereas MpkA plays a major role (Jain et al., 2011) [66] and this deficiency increases production of siderophore. 

Fig 3: Regulation of iron homeostatis in A. fumigates (A) SreA and HapX mediated iron regulation. (B) A. fumigatus Phenotypes i.e., SreA (Δ sreA) and HapX (Δ hapX) deficient flask mutant strains in 24h/37˚C cultures. During iron starvation, in contrast to the wild type (wt), due to accumulation of protoporphyrin IX, Δ hapX mycelia are reddish colored and in iron sufficiency, Δ sreA mycelia are reddish colored due to accumulation of heme, iron, and FC (Schrettl et al., 2008, 2010a) [59,60].

Table 6: Regulatory functions of Central transcriptional factors involved in Iron Homeostasis of A. fumigates:

6. Iron acquisition and storage in A. fumigatus:

For host iron sources, A. fumigatus lacks particular uptake systems such as heme, Transferring or ferritin. To mobilize extracellular iron, it excretes fusarinine C (FsC) and triacetylfusarinine C (TAFC) (Table 5). Following to  iron chelation, the ferric forms (fe III) of Fs C and TAFC are taken up by Specific Iron Transporters (SIT) (Haas., et al., 2003) and for storage and distribution of iron consists of two different siderophores excretes intracellularly such as hyphal ferricrocin (FC) and conidial hydroxyferricrocin (HFC) shown in (Table 5) (Schrettl., et al., 2007 and Wallner., et al., 2009).

For release of iron, the siderophores are intracellularly hydrolyzed (Almeida., et al., 2009) and the iron is transferred or stored to the metabolic machinery. In fungi, four types of different mechanisms for iron acquisition have been identified, they are: (Haas., et al., 2008).

• Uptake of specific iron chelators of ferric iron known as siderophores

• low-affinity ferrous iron uptake 

• uptake of heme and degradation 

• Reductive Iron Assimilation (RIA)

SIT constitutes a subfamily of the major facilitator superfamily of protein acting most probably vitalized by the plasma membrane potential as proton symporters Philpott and Protchenko., 2008) [67]. In the fungal kingdom, SIT attributes uptake of iron visualizes to be protected universally [68, 69]. Iron supply is ensured by low affinity ferrous iron acquisition, reductive iron assimilation (RIA), two high affinity iron uptake systems, siderophore mediated iron uptake [70].

Additionally, A. fumigatus employs vacuolar iron storage and CccA expression indicated by the iron inducible system [59]. During infection, removal of iron from host sources such as transferring by iron acquisition plays major role in A. fumigatus siderophores [71,72].

 The ferrous iron which is reduced is reoxidized and imported consisting of the ferroxidase FetC and the iron permease FtrA by a protein complex. RIA starts with ferriciron reduction to the high soluble ferrous iron by plasma membrane localized metallo reductases [73]. A. fumigatus encodes putative metalloreductases FreB has involved in Reductive Irion Assimilation indicating possible enzyme dismissal. Blocking of this RIA (Δ ftrA mutant) does not have any effect of A. fumigatus virulence.

In order to overcome the stages of iron toxicity and iron limiting conditions iron-limitation as well as to avoid iron toxicity (Table 3), iron should be stored in cells. To maintain as such there as two types of strategies involved:

1. Iron deposition in vacuoles and 

2. siderophore-mediated iron storage [59] and [74]

For storage of iron, A. fumigates engage in both vacuolar iron deposition and intracellular siderophores [75]

7.  Iron transport mechanisms in A. fumigatus:

In general, iron transport channels for siderophore mediated have four different types of mechanisms and the fungal species involved in this transport are shown in (Table 7) [76]:

1. Shuttle mechanism

2. Taxicab mechanism

3. Hydrolytic mechanism

4. Reductive mechanism

Shuttle mechanism:  From the ligand the ferrous oxide (Fe-III) is released and reduced by reductive enzymes and the siderophores which are free are then recycled, whereas siderophore complex- ferrous oxide is transported across the cell membrane [77].

Taxicab mechanism: Ferrous oxide (Fe-III) transfers cell membrane from the extracellular siderophores to intracellular ligands [78]

 Hydrolytic mechanism: To release the ferrous oxide (Fe III) the complete Fe (III)–siderophore complex is transported into the cell which is related to degradative and several reductive process. Inside the cell, Ferrous oxide is reduced to Ferric oxide and then siderophore is again excreted [79].

Reductive mechanism: Siderophore complex of Fe (III) does not transport across the cell membrane. The reduced iron is taken up by the cell soon after the reduction of ferrous oxide to ferric oxide at the cell membranes [80].

Table 7: Iron transport mechanisms in fungal siderophores

(Ahmad and Holmostrom 2014)

8. PATENTS:

Patents granted on the detection of siderophores in Aspergillus fumigatus were listed below in table 8

Table 8: List Of Patents Granted on Detection of A. fumigatus

A. fumigatus saprophytic fungi play an unpleasant role in human organs as a invasive aspergillosis. The both extracellular and intracellular siderophores togetherly plays as an important function of A. fumigatus virulence in a invasive pulmonary aspergillosis of murine model, but blocking of metalloreductase FreB mutant involves in RIA for the great affinity manner to acquire iron. 

Srb A was found to be active siderophore, as this deficiency leads to decrease in ergosterol content. Furthermore, this leads to low level of resistance in against azole drugs. Therefore, ergosterol biosynthetic pathway should be highly improved for the best diagnosis of fungal infections hostile to humans and through this mortality rate can also be low. 

 In general, fungal siderophores transports Iron uptake in different mechanisms for the absorption and regulation of ferrous form of ions (feII), that may be predictable in A. fumigatus in future perspectives. 

Funding: No funding sources 

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee of Biological Sciences, Allahabad

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