Iron and siderophores in fungal–host interactions

Johnson, Linda J.

doi:10.1016/j.mycres.2007.11.012

Cited by 153 publications

(127 citation statements)

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“…Studies of yeast have revealed that the biosynthesis of siderophores is positively regulated during iron deficiency (14,19,33,50). Previous reports had suggested a constitutive production of ferrichrome in S. pombe (45,46).…”

Section: Discussionmentioning

confidence: 99%

Iron-Dependent Remodeling of Fungal Metabolic Pathways Associated with Ferrichrome Biosynthesis

Mercier

Labbé

2010

Appl Environ Microbiol

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The fission yeast Schizosaccharomyces pombe excretes and accumulates the hydroxamate-type siderophore ferrichrome. The sib1 ؉ and sib2 ؉ genes encode, respectively, a siderophore synthetase and an L-ornithine N 5 -oxygenase that participate in ferrichrome biosynthesis. In the present report, we demonstrate that sib1 ؉ and sib2 ؉ are repressed by the GATA-type transcriptional repressor Fep1 in response to high levels of iron. We further found that the loss of Fep1 results in increased ferrichrome production. We showed that a sib1⌬ sib2⌬ mutant strain exhibits a severe growth defect on iron-poor media. We determined that two metabolic pathways are involved in biosynthesis of ornithine, an obligatory precursor of ferrichrome. Ornithine is produced by hydrolysis of arginine by the Car1 and Car3 proteins. Although car3 ؉ was constitutively expressed, car1 ؉ transcription levels were repressed upon exposure to iron, with a concomitant decrease of Car1 arginase activity. Ornithine is also generated by transformation of glutamate, which itself is produced by two separate biosynthetic pathways which are transcriptionally regulated by iron in an opposite fashion. In one pathway, the glutamate dehydrogenase Gdh1, which produces glutamate from 2-ketoglutarate, was repressed under iron-replete conditions in a Fep1-dependent manner. The other pathway involves two coupled enzymes, glutamine synthetase Gln1 and Fe-S cluster-containing glutamate synthase Glt1, which were both repressed under iron-limiting conditions but were expressed under iron-replete conditions. Collectively, these results indicate that under conditions of iron deprivation, yeast remodels metabolic pathways linked to ferrichrome synthesis in order to limit iron utilization without compromising siderophore production and its ability to sequester iron from the environment.

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Section: Discussionmentioning

confidence: 99%

Iron-Dependent Remodeling of Fungal Metabolic Pathways Associated with Ferrichrome Biosynthesis

Mercier

Labbé

2010

Appl Environ Microbiol

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“…Consequently, sequestration of free iron by the host is a key factor for inhibiting the virulence of microbial pathogens (6)(7)(8). Furthermore, most successful pathogens have evolved mechanisms to obtain iron while inside the host.…”

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confidence: 99%

Divergent Targets of Aspergillus fumigatus AcuK and AcuM Transcription Factors during Growth In Vitro versus Invasive Disease

Pongpom

Liu

et al. 2015

Infect Immun

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eIn Aspergillus nidulans, the AcuK and AcuM transcription factors form a complex that regulates gluconeogenesis. In Aspergillus fumigatus, AcuM governs gluconeogenesis and iron acquisition in vitro and virulence in immunosuppressed mice. However, the function of AcuK was previously unknown. Through in vitro studies, we found that A. fumigatus ⌬acuK single and ⌬acuK ⌬acuM double mutants had impaired gluconeogenesis and iron acquisition, similar to the ⌬acuM mutant. Also, the ⌬acuK, ⌬acuM, and ⌬acuK ⌬acuM mutants had similar virulence defects in mice. However, the ⌬acuK mutant had a milder defect in extracellular siderophore activity and induction of epithelial cell damage in vitro than did the ⌬acuM mutant. Moreover, overexpression of acuM in the ⌬acuK mutant altered expression of 3 genes and partially restored growth under iron-limited conditions, suggesting that AcuM can govern some genes independently of AcuK. Although the ⌬acuK and ⌬acuM mutants had very similar transcriptional profiles in vitro, their transcriptional profiles during murine pulmonary infection differed both from their in vitro profiles and from each other. While AcuK and AcuM governed the expression of only a few iron-responsive genes in vivo, they influenced the expression of other virulence-related genes, such as hexA and dvrA. Therefore, in A. fumigatus, while AcuK and AcuM likely function as part of the same complex, they can also function independently of each other. Furthermore, AcuK and AcuM have different target genes in vivo than in vitro, suggesting that in vivo infection stimulates unique transcriptional regulatory pathways in A. fumigatus. Aspergillus fumigatus causes a variety of diseases, including allergic bronchopulmonary aspergillosis, aspergilloma, invasive pulmonary aspergillosis, and hematogenously disseminated aspergillosis (1, 2). The incidence of invasive aspergillosis is rising due to the increasing number of immunocompromised patients, who are at risk for this disease (3, 4). Furthermore, because invasive aspergillosis remains difficult to diagnose and treat, this infection is still associated with significant mortality (5). One approach to developing new strategies to treat this frequently deadly infection is to target the factors that enable A. fumigatus to survive and proliferate within the host.Iron is an essential trace element for most living organisms, including pathogenic microorganisms. Consequently, sequestration of free iron by the host is a key factor for inhibiting the virulence of microbial pathogens (6-8). Furthermore, most successful pathogens have evolved mechanisms to obtain iron while inside the host. For example, A. fumigatus acquires iron from the host by both reductive iron assimilation and secretion of siderophores (9-11). Siderophore secretion is more important for growth within the host, because A. fumigatus mutants with defects in siderophore synthesis have dramatically attenuated virulence, whereas those with defects in reductive iron assimilation do not (11-13).Previously, we determined tha...

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“…Second, hydroxamate siderophores are acutely important to pathogenic fungi, which are not known to make catecholate or other types of chelating moieties. Many fungi, lacking ferritin, use variants of the same hydroxamate siderophore for both uptake and subsequent intracellular trafficking and storage functions (12)(13)(14). For viability and virulence, Aspergillus species, including deadly strains of Aspergillus fumigatus, have been shown to depend on functional pathways for biosynthesis of ferricrocin and fusarinine, siderophores involved in extracellular iron uptake and intracellular storage.…”

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confidence: 99%

Comprehensive Spectroscopic, Steady State, and Transient Kinetic Studies of a Representative Siderophore-associated Flavin Monooxygenase

Mayfield

Frederick

Streit

et al. 2010

Journal of Biological Chemistry

113

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Iron and siderophores in fungal–host interactions

Cited by 153 publications

References 118 publications

Iron-Dependent Remodeling of Fungal Metabolic Pathways Associated with Ferrichrome Biosynthesis

Iron-Dependent Remodeling of Fungal Metabolic Pathways Associated with Ferrichrome Biosynthesis

Divergent Targets of Aspergillus fumigatus AcuK and AcuM Transcription Factors during Growth In Vitro versus Invasive Disease

Comprehensive Spectroscopic, Steady State, and Transient Kinetic Studies of a Representative Siderophore-associated Flavin Monooxygenase

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