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.
Highlights
A non-fumagillin producer mutant strain caused significantly less cellular damage than the wild type in vitro, demonstrating a potential relevance of this toxin in virulence [23]. Given these previous data and the need to deeply analyze the involvement of secondary metabolites in virulence [25], the aim of the present study was to assess the role of fumagillin in the pathogenesis of A. fumigatus
We studied the effect of commercial fumagillin on A. fumigatus itself, macrophages, and epithelial cells
The strain ∆fmaA::fmaA secreted an average concentration of 0.25 μg/mL fumagillin, the concentration of fumagillin secreted was higher than that produced by the Wt in 25%
Summary
The conidia allow A. fumigatus to reach all chambers of the human respiratory tract, where the fungus is able to cause a wide range of infections depending on the immune status of the patient [3,4,5,6]. The biological characteristics that allow A. fumigatus to colonize and/or infect the respiratory tract are known as virulence factors. These include the fungal cell wall and the proteins involved in its formation, the resistance of the conidia to ultraviolet radiation and dryness, the mechanisms to evade the immune response, and the production of proteases and toxins [6]. Among the variety of toxins produced by A. fumigatus, several have been linked with enhanced virulence and include gliotoxin [12,13,14,15], fumitremorgin A and B [16,17], hexadehydroastechrome [18], hemolysin, and mitogillin [19]
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