Secretion of a fungal protease represents a complement evasion mechanism in cerebral aspergillosis

Area of Science:

• Neuroimmunology
• Mycology
• Infectious Diseases

Background:

• Cerebral aspergillosis has high mortality, suggesting ineffective brain immune responses.
• Complement system is crucial for antifungal immunity but appears deficient in cerebral aspergillosis.
• Aspergillus species may evade immune attack by degrading complement proteins.

Purpose of the Study:

• To investigate if Aspergillus produces proteases that degrade complement proteins in the cerebrospinal fluid (CSF).
• To understand how Aspergillus-derived proteases affect complement-mediated fungal clearance and phagocytosis.
• To explore strategies for restoring complement function against cerebral aspergillosis.

Main Methods:

• Culturing Aspergillus in CSF to mimic brain conditions and analyzing secreted proteases.
• Assessing the effect of Aspergillus proteases on complement protein activity and fungal opsonization.
• Evaluating the impact of proteases on complement receptor CR3 expression on immune cells.
• Testing the efficacy of nitrogen source supplementation (glutamine, arginine) in preventing complement degradation.

Main Results:

• Aspergillus secretes a protease that degrades various complement proteins in CSF, with Aspergillus fumigatus being particularly effective.
• This degradation significantly reduces the opsonization of fungal hyphae and diminishes complement receptor CR3 on granulocytes and microglia.
• The protease activity impairs phagocytosis by microglia.
• Supplementation of CSF with nitrogen sources, especially glutamine or arginine, rescues complement proteins and prevents their cleavage.

Conclusions:

• Aspergillus proteases play a key role in evading the host complement system during cerebral aspergillosis.
• Restoring complement function by inhibiting protease activity or supplementing with specific nitrogen sources shows therapeutic potential.
• Targeting Aspergillus-derived proteases or using supportive nutrient therapy could reduce the lethality of cerebral aspergillosis.