Metabolic characterisation of Aspergillus fumigatus clinical isolates

Fungal infections caused by opportunistic pathogens such as Aspergillus fumigatus, are estimated to kill more people annually than malaria and tuberculosis. Nutrient acquisition and subsequent metabolic processes, such as carbon and nitrogen catabolite repression (CCR, NCR) are important for colonisation and promoting fungal survival within the human host and have profound effects on virulence traits such as cell wall composition and enzyme secretion. The aim of this work was therefore to investigate metabolic aspects in thirteen A. fumigatus clinical isolates and establish a relationship with virulence. In a neutropenic mouse model, all strains, except for three, presented the same degree of virulence. No correlation between virulence and CCR or NCR was observed, despite strain-specific differences in protease secretion, phenotypic growth and CCR drug resistance. Metabolome analysis in the presence of different carbon sources was carried out for the protease hyper-secretion strain Afs35 and compared to the routinely used laboratory strain CEA10. Intracellular sugars, that can serve as precursors for cell wall polysaccharides, were significantly increased in strain Afs35. This strain was more sensitive to cell wall perturbing agents and conidia were less phagocytised by macrophages when compared to strain CEA10, indicating substantial differences in cell wall organisation and structure between both strains. Despite these differences, both strains were equally virulent in a neutropenic murine model and elicited the same in vitro immune response. Furthermore, protease secretion was shown to be inhibited under hypoxic conditions, that are predicted to occur at defined locations within the human host, suggesting that protease secretion may not be essential for infection. In conclusion, great metabolic plasticity exists between A. fumigatus clinical strains and further investigation into this trait, as well as how it is affected by the underlying immune system disturbance, is required in order to develop new avenues for combatting systemic fungal infections.

Financial support: FAPESP and CNPq, Brazil