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Aspergillus fumigatus Fumagillin Contributes to Host Cell Damage
Xabier Guruceaga1, Uxue Perez-Cuesta1, Aize Pellon2
1Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
Abstract:
The activity of fumagillin, a mycotoxin produced by Aspergillus fumigatus, has not been studied in depth. In this study, we used a commercial fumagillin on cultures of two cell types (A549 pneumocytes and RAW 264.7 macrophages). This toxin joins its target, MetAP2 protein, inside cells and, as a result, significantly reduces the electron chain activity, the migration, and the proliferation ability on the A549 cells, or affects the viability and proliferation ability of the RAW 264.7 macrophages. However, the toxin stimulates the germination and double branch hypha production of fungal cultures, pointing out an intrinsic resistant mechanism to fumagillin of fungal strains. In this study, we also used a fumagillin non-producer A. fumigatus strain (∆fmaA) as well as its complemented strain (∆fmaA::fmaA) and we tested the fumagillin secretion of the fungal strains using an Ultra High-Performance Liquid Chromatography (UHPLC) method. Furthermore, fumagillin seems to protect the fungus against phagocytosis in vitro, and during in vivo studies using infection of immunosuppressed mice, a lower fungal burden in the lungs of mice infected with the ∆fmaA mutant was demonstrated.
Insights
Fumagillin, a mycotoxin from Aspergillus fumigatus, inhibits human cell functions but promotes fungal growth, indicating a fungal resistance mechanism. A fumagillin-deficient mutant showed reduced fungal burden in vivo.
Area of Science:
- Mycology
- Cell Biology
- Biochemistry
Background:
- Fumagillin, a mycotoxin from Aspergillus fumigatus, has incompletely understood activities.
- Its molecular target is methionine aminopeptidase 2 (MetAP2).
Purpose of the Study:
- To investigate the effects of fumagillin on human cell lines and fungal growth.
- To explore the role of fumagillin in Aspergillus fumigatus pathogenesis and self-resistance.
Main Methods:
- Treatment of A549 pneumocytes and RAW 264.7 macrophages with commercial fumagillin.
- Utilizing a fumagillin non-producer Aspergillus fumigatus strain (∆fmaA) and its complemented strain (∆fmaA::fmaA).
- Analysis of fungal secretion using Ultra High-Performance Liquid Chromatography (UHPLC).
- In vitro phagocytosis assays and in vivo infection models in immunosuppressed mice.
Main Results:
- Fumagillin reduced electron transport chain activity, migration, and proliferation in A549 cells.
- Fumagillin affected viability and proliferation in RAW 264.7 macrophages.
- Fumagillin stimulated fungal germination and hyphal growth, suggesting intrinsic fungal resistance.
- The ∆fmaA mutant exhibited a lower fungal burden in mouse lungs compared to wild-type.
- Fumagillin appeared to protect fungi against phagocytosis in vitro.
Conclusions:
- Fumagillin exhibits differential effects on host cells and the producing fungus.
- Aspergillus fumigatus possesses intrinsic mechanisms for fumagillin resistance.
- Fumagillin may play a role in fungal pathogenesis by inhibiting host immune responses and promoting fungal survival.
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