Aspergillus fumigatus Fumagillin Contributes to Host Cell Damage

Guruceaga, Xabier; Perez-Cuesta, Uxue; Pellón, Aize; Cendon-Sanchez, Saioa; Pelegri-Martinez, Eduardo; González, Oskar; Hernando, Fernando; Mayayo, Emilio; Anguíta, Juan; Alonso, Rosa M.; Keller, Nancy P.; Ramirez‐Garcia, Andoni; Rementerı́a, Aitor

doi:10.3390/jof7110936

Cited by 6 publications

(9 citation statements)

References 43 publications

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“…The second question involves why pseurotin A is regulated by gliotoxin metabolism. As we described, FumR regulates both the pseurotin A and fumagillin biosynthesis pathways, and fumagillin biosynthesis has been reported to be involved in the pathogenesis of A. fumigatus 51 . Although our report is focused on pseurotin A biosynthesis, fumagillin biosynthesis is also regulated in a gliotoxin-negative manner.…”

Section: Discussionmentioning

confidence: 65%

Regulation of pseurotin A biosynthesis by GliZ and zinc in Aspergillus fumigatus

Seo

Kang

Lee

et al. 2023

Sci Rep

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Recently, we reported that zinc regulates gliotoxin biosynthesis via ZafA, which is a zinc-responsive transcriptional activator. From an HPLC analysis of culture media of Aspergillus fumigatus, we found a trend of decreasing gliotoxin production but increasing pseurotin A and fumagillin production in proportion to the zinc concentration. The expression of the genes involved in pseurotin A biosynthesis was upregulated under high zinc concentrations. Furthermore, upregulated expression of pseurotin A biosynthetic genes and higher production of pseurotin A were observed in the zafA deletion strain. Interestingly, the deletion of gliZ, a transcriptional activator of gliotoxin biosynthesis genes, resulted in upregulated expression of pseurotin A biosynthetic genes and increased production of pseurotin A. We detected upregulation of fumR expression in the gliZ and zafA deletion mutants. The overexpression of gliZ observed in the zafA deletion mutant resulted in the failure of the mutant to increase pseurotin A production, which is a phenotype of the zafA deletion mutant. These results suggest that ZafA sequentially regulates pseurotin A biosynthesis through GliZ. Finally, we found through a murine virulence test that the gliZ and fumR double-deletion mutants showed a delayed death rate compared with the single-deletion mutants of either gliZ or fumR. Taken together, these results suggested that the biosynthesis of gliotoxin and pseurotin A are regulated in opposite ways by zinc utilization and that each secondary metabolite is synthesized when the synthesis of another secondary metabolite fails to protect it against the defense system of the host.

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Section: Discussionmentioning

confidence: 65%

Regulation of pseurotin A biosynthesis by GliZ and zinc in Aspergillus fumigatus

Seo

Kang

Lee

et al. 2023

Sci Rep

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“…To understand the behavior of the fungal strains in contact with the murine macrophages cell line RAW 264.7 we followed the method previously described (30). Briefly, 2 × 10 5 cells/ml in 500 µL of cell culture RPMI (RPMI 1640 medium supplemented with 10% heat-inactivated FBS, 200 mM L-glutamine, 100 U/ml penicillin and 0.1 mg/ml streptomycin) were seeded in 24-well plates which contained 12 mm-diameter coverslips.…”

Section: Methodsmentioning

confidence: 99%

TheAspergillus fumigatus maiAgene contributes to cell wall homeostasis and fungal virulence

Guruceaga,

Perez-Cuesta,

Martin-Vicente

et al. 2023

Preprint

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In this study, two distinct in vitro infection models of Aspergillus fumigatus, using murine macrophages (RAW264.7) and human lung epithelial cells (A549), were employed to identify the genes important for fungal adaptation during infection. Transcriptomic analyses of co-incubated Aspergillus uncovered 140 fungal genes up-regulated in common between both models that, when compared with a previously published in vivo transcriptomic study, allowed the identification of 13 genes consistently up-regulated in all three infection conditions. Among them, the maiA gene, responsible for a critical step in the L-phenylalanine degradation pathway, was identified. Disruption of maiA resulted in a mutant strain unable to complete the Phe degradation pathway, leading to an excessive production of pyomelanin when this amino acid served as the sole carbon source. Moreover, the disruption mutant exhibited noticeable cell wall abnormalities, with reduced levels of β-glucans within the cell wall. the maiA-1 mutant strain induced reduced inflammation in primary macrophages and displayed significantly lower virulence in a neutropenic mouse model of infection. This is the first study linking the A. fumigatus maiA gene to fungal cell wall homeostasis and virulence.

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“…While gliotoxin promotes host cell apoptosis (see Section 3.2), fumagillin was shown to reduce macrophage viability, indicating that fumagillin contributes to macrophage damage and may thus promote fungal escape (Guruceaga et al, 2021).…”

Section: Lytic Escapementioning

confidence: 99%

“…A. fumigatus secretes secondary metabolites, including several non‐peptide mycotoxins like fumagillin or gliotoxin (Latge, 1999). While gliotoxin promotes host cell apoptosis (see Section 3.2), fumagillin was shown to reduce macrophage viability, indicating that fumagillin contributes to macrophage damage and may thus promote fungal escape (Guruceaga et al, 2021).…”

Section: Escape From Macrophagesmentioning

confidence: 99%

“We've got to get out”—Strategies of human pathogenic fungi to escape from phagocytes

Sonnberger,

Kasper,

Lange

et al. 2023

Molecular Microbiology

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Human fungal pathogens are a deadly and underappreciated risk to global health that most severely affect immunocompromised individuals. A virulence attribute shared by some of the most clinically relevant fungal species is their ability to survive inside macrophages and escape from these immune cells. In this review, we discuss the mechanisms behind intracellular survival and elaborate how escape is mediated by lytic and non‐lytic pathways as well as strategies to induce programmed host cell death. We also discuss persistence as an alternative to rapid host cell exit. In the end, we address the consequences of fungal escape for the host immune response and provide future perspectives for research and development of targeted therapies.

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Aspergillus fumigatus Fumagillin Contributes to Host Cell Damage

Cited by 6 publications

References 43 publications

Regulation of pseurotin A biosynthesis by GliZ and zinc in Aspergillus fumigatus

Regulation of pseurotin A biosynthesis by GliZ and zinc in Aspergillus fumigatus

TheAspergillus fumigatus maiAgene contributes to cell wall homeostasis and fungal virulence

“We've got to get out”—Strategies of human pathogenic fungi to escape from phagocytes

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