Targeting zinc homeostasis to combat Aspergillus fumigatus infections

Vicentefranqueira, Rocío; Amich, Jorge; Laskaris, Paris; Ibrahim-Granet, Oumaïma; Latgé, Jean Paul; Toledo, Héctor; Leal, Fernando; Calera, José Antonio

doi:10.3389/fmicb.2015.00160

Cited by 23 publications

(29 citation statements)

References 44 publications

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“…The difference in growth of this mutant compared to ZafA-deficient A. fumigatus may be due to low level constitutive (ZafA-independent) expression of Zrf transporters on the ZafA mutant, which are completely absent in ZrfABC-deficient strain (49). Due to its importance in both pulmonary and corneal infections, ZafA may be a target for anti-fungal therapies (50). …”

Section: Discussionmentioning

confidence: 99%

“…Therefore, treatment with CP could represent a therapeutic strategy for neutropenic patients with fungal infections. Overall, these studies suggest that inhibiting fungal Zn and Mn acquisition through chelators, such as calprotectin, or through new inhibitors of ZafA or other components Zn and Mn transport may represent a new therapeutic approach (50). …”

Section: Discussionmentioning

confidence: 99%

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Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection

Clark

Jhingran

Sun

et al. 2016

The Journal of Immunology

128

110

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Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein which possesses anti-microbial activity primarily due to its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectin-deficient S100A9 −/− mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro, and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9−/− mice by injecting recombinant calprotectin. Further, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin’s anti-hyphal activity. In contrast to hyphae, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro, or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus ΔzafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared to wild-type. Collectively, these studies demonstrate a novel stage - specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection

Clark

Jhingran

Sun

et al. 2016

The Journal of Immunology

128

110

View full text Add to dashboard Cite

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“…Gene zrfC is required to overcome the inhibitory effect of calprotectin (39). Thus, zrfC plays a dual role in fungal virulence; in other words, it is important for the uptake of zinc and also counteracting the inhibitory effect of CP (35).…”

Section: Zinc Uptakementioning

confidence: 99%

“…For the optimal growth of fungi, the availability of free zinc in living tissues is limited, since they are bound to proteins. For the uptake of zinc from a living host, A. fumigatus uses zinc transporters (35). The genome of A. fumigatus consists of three putative zinc transporterencoding genes (zrfA, zrfB and zrfC).…”

Section: Zinc Uptakementioning

confidence: 99%

Molecular Insights into Pathogenesis and Infection with Aspergillus fumigatus

Ghazaei¹

2017

MJMS

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The virulence of fungi is dependent on multiple factors, including the immune status of patients and biological features of fungi. In particular, the virulence of Aspergillus fumigatus is due to the complex interaction among various molecules involved in thermotolerance (such as ribosomal biogenesis proteins, α-mannosyltransferase and heat shock proteins), pigment production (DHN-melanin), immune evasion (like melanin and hydrophobin) and nutrient uptake (such as siderophores and zinc transporters). Other molecules also play important roles in the virulence of A. fumigatus, including cell wall components and those which maintain its integrity (for instance β-1-3 glucan, α-1-3 glucan, chitin, galactomannan and mannoproteins) and adhesion (such as hydrophobins), as well as various hydrolytic enzymes (such as serine and aspartic protease, phospholipases, metalloproteinase and dipeptidyl peptidases). Signalling molecules (including G-protein, cAMP, Ras protein and calcineurin) also increase the virulence through altering the metabolic response to stress conditions and toxins (such as gliotoxin, fumitremorgins, fumagatin and helvolic acid).

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“…Zinc uptake is induced by the zafA transcriptional activator under Zn-limiting conditions, and its deletion abrogates A. fumigatus virulence (10). Hence, by reducing the availability of zinc, the growth of A. fumigatus might be inhibited, which could have clinical applications as suggested recently (11). In this regard, the nonspecific chelator EDTA has been successfully tested in vitro against Aspergillus (12).…”

mentioning

confidence: 99%

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

Laskaris

Atrouni

Calera

et al. 2016

Antimicrob Agents Chemother

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f Aspergillus fumigatus can infect immunocompromised patients, leading to high mortality rates due to the lack of reliable treatment options. This pathogen requires uptake of zinc from host tissues in order to successfully grow and cause virulence. Reducing the availability of that micronutrient could help treat A. fumigatus infections. In this study, we examined the in vitro effects of seven chelators using a bioluminescent strain of A. fumigatus. 1,10-Phenanthroline and N,N,N=,N=-tetrakis(2-pyridylmethyl) ethane-1,2-diamine (TPEN) proved to be the chelators most effective at inhibiting fungal growth. Intraperitoneal administration of either phenanthroline or TPEN resulted in a significant improvement in survival and decrease of weight loss and fungal burden for immunosuppressed mice intranasally infected with A. fumigatus. In vitro both chelators had an indifferent effect when employed in combination with caspofungin. The use of TPEN in combination with caspofungin also significantly increased survival compared to that when using these drugs individually. Our results suggest that zinc chelation may be a valid strategy for dealing with A. fumigatus infections and that both phenanthroline and TPEN could potentially be used either independently or in combination with caspofungin, indicating that their use in combination with other antifungal treatments might also be applicable.A spergillus fumigatus is a widespread soil-dwelling fungal saprotroph (1). It is one of the most ubiquitous fungal species with airborne conidia, and it is estimated that all humans inhale several hundred conidia each day (2). These are completely innocuous to immunocompetent hosts. However, the conidia are able to develop and cause invasive pulmonary aspergillosis (IPA) in immunocompromised individuals (3). This disease is difficult to treat, with a mortality rate of 45.6% (4). Commonly used drug treatment options include triazoles such as voriconazole, which inhibit ergosterol synthesis, amphotericin B, which binds to ergosterol and thus results in increased permeability of the cell membrane, and echinocandins such as caspofungin, which inhibit glucan synthesis (5).Both fungal and bacterial pathogens require cations to grow within their hosts and utilize specialized mechanisms in order to obtain them (6). Zinc is considered essential for all organisms, including pathogens (7). The average concentration of free Zn 2ϩ in human serum is 0.08 M, which is about 150 times lower than the minimal concentration required for A. fumigatus to grow optimally in a defined liquid medium (8). A. fumigatus possesses three genes, zrfA, zrfB, and zrfC, encoding plasma membrane zinc transporters (8). The zrfA and zrfB genes are required for zinc uptake in acidic Zn-limited environments (7), while zrfC is required for zinc uptake in alkaline environments (9) The zrfC gene is primarily responsible for zinc acquisition within a host's lungs and is required for virulence; zrfA and zrfB contribute to fungal pathogenesis to a lesser extent than zrfC and are not r...

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Targeting zinc homeostasis to combat Aspergillus fumigatus infections

Cited by 23 publications

References 44 publications

Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection

Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection

Molecular Insights into Pathogenesis and Infection with Aspergillus fumigatus

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

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