Pathogenic fungi produce proteases to degrade cerebral immune proteins and to evade immune attack
Abstract number: P1355
Rambach G., Dum D., Mohsenipour I., Lass-Flörl C., Rainer J., Würzner R., Dierich M.P., Speth C.
Objectives: Affection of the central nervous system (CNS) in the course of a fungal infection is fatal in the majority of cases. In order to determine the reasons for the incomplete elimination of invading fungi we examined the fungal capacity to degrade complement proteins and cytokines as well as functional surface molecules of immune cells in the CNS.
Methods:Aspergillus spp. and other pathogenic fungi were grown in medium or cerebrospinal fluid (CSF), with or without supplements. Degradation of soluble immune proteins was investigated by Western Blot. Hyphal opsonisation was examined by immunofluorescence. Cellular expression of surface proteins was quantified by FACS.
Results: The growth of Aspergillus spp. in CSF resulted in secretion of proteolytic factors which degraded complement proteins. The extent of the proteolysis was dependent on the time period of fungal growth and the Aspergillus species. A. fumigatus, the predominant cause of cerebral aspergillosis, induced a rather quick and strong degradation, whereas the proteolysis by A. terreus supernatants was weaker and rather slow. The fungal secretion of proteases correlated with a diminished opsonisation of Aspergillus hyphae by complement proteins, suggesting a better protection against phagocytosis. Furthermore the proteolytic factors attack complement receptor CR3 (CD11b/CD18) and MHC on the surface of immune cells and thus interfere with efficient phagocytosis and antigen presentation. The secretion of proteases as effective immune evasion mechanism could also be detected for isolates of the Pseudallescheria group and for zygomycetes (Rhizomucor pusillus, Rhizopus microsporus).
In order to develop therapeutic approaches that interfere with fungal proteases and thus with immune evasion we investigated the influence of culture conditions on the secretion of proteases. The addition of various nitrogen sources to CSF prevented the secretion of these proteases. Glutamin as endogenous substance was tested in detail and was found to effectively interfere with protease secretion in a dose-dependent manner. Furthermore, first experiments using protease inhibitors showed promising results.
Conclusion:Aspergillus and other pathogenic fungi secrete proteases which may play a significant role in immune evasion by degrading complement and surface-bound molecules of cerebral immune cells. These proteases represent an interesting therapeutic target to decrease the lethality of cerebral aspergillosis.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
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