Gliotoxin is an important virulence factor in cerebral aspergillosis
Abstract number: O245
Speth C., Kupfahl C., Hagleitner M., Deutinger M., Rambach G., Mohsenipour I., Dierich M.P.
Objective: The high lethality of cerebral aspergillosis urgently asks for a deeper insight into the pathogenic mechanisms of this disease. Therefore we studied whether mycotoxins, especially gliotoxin, contribute to neural damage and to the inefficient immune response in cerebral aspergillosis. Furthermore we tested the putative capacity of antioxidant components to interfere with the harmful activity of gliotoxin.
Methods: The secretion of gliotoxin after fungal growth in cerebrospinal fluid (CSF) was measured using HPLC and tandem mass spectrometry. An effect of gliotoxin on the viability and proliferation of astrocytes, neurons and microglia was tested by MTS assays. Phagocytic activity of cells in the presence of gliotoxin was quantified using fluorescent latex beads and subsequent microscopic analysis; oxidative burst was studied by FACS.
Results: Pathogenic Aspergillus species like A. fumigatus secrete significant levels of gliotoxin when cultivated in CSF. The corresponding concentration of gliotoxin was sufficient to affect the viability of astrocytes, neurons and microglial cells, with neurons and microglia being the most sensitive cell types. Subtoxic concentrations of gliotoxin diminished the capacity of microglia to phagocyte pathogens. Furthermore gliotoxin exaggerated the oxidative burst in infiltrating granulocytes induced by stimuli such as PMA.
Therapeutic approaches might aim to neutralize the inhibitory or even toxic effect of gliotoxin and thus to reconstitute the potency of cerebral immunity. We used glutathione for this purpose, a tripeptide made up from cysteine, glutamate and glycin which act as a reducing compound. In first promising experiments with glutathione we were able to protect brain cells from gliotoxin concentrations which otherwise were shown to kill the cells. Furthermore glutathione reconstituted the phagocytic activity of immune cells in the presence of gliotoxin.
Conclusions: These data indicate an essential contribution of gliotoxin to the pathogenesis of cerebral aspergillosis. As a therapeutic approach neuroprotective substances such as glutathione might be used to neutralize the toxic or immune-inhibitory activity of gliotoxin.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
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