Gliotoxin as putative virulence factor and immunotherapeutic target in a cell culture model of cerebral aspergillosis

The mycotoxin gliotoxin is an important metabolite produced by Aspergillus fumigatus, but its precise role in the pathogenesis of cerebral aspergillosis is not yet determined. We could demonstrate that growth in cerebrospinal fluid (CSF) induced the production and secretion of significant amounts of gliotoxin by A. fumigatus. These concentrations of 590-720 nM were sufficient to reduce the viability of astrocytes and neurons, as well as of primary microglia, already after few hours of incubation. Annexin staining and electron microscopy revealed the induction of apoptosis rather than necrosis as the relevant mode of gliotoxin action in the brain. Furthermore, even a low gliotoxin concentration of 100 nM, which was subtoxic for astrocytes, was able to significantly down-modulate the phagocytic capacity of astrocytes.In order to improve the current antimycotic therapy of cerebral aspergillosis by supporting innate immunity in the fight against Aspergillus, we aimed to neutralize the toxic potency of gliotoxin towards different brain cell types. Compounds such as dithiothreitol (DTT) or glutathione that reduce the internal disulfide bond of gliotoxin were shown here to be able to interfere with the gliotoxin-induced decrease of cell viability and to save the cells from induction of apoptosis. Thus, exploration of these substances may lead to novel approaches for adjunctive treatment of cerebral aspergillosis.

► Gliotoxin is produced by Aspergillus fumigatus grown under CNS conditions. ► Gliotoxin induces apoptosis of brain cells. ► Subtoxic concentrations of gliotoxin impair phagocytic activity of astrocytes. ► Reducing compounds might be used as putative therapeutics to inactivate gliotoxin.