Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

Area of Science:

• Mycology
• Immunology
• Hematology

Background:

• Invasive fungal infections by Aspergillus and Mucorales species are life-threatening in immunocompromised individuals.
• Understanding fungal interactions with innate immunity, like complement and platelets, is crucial for effective therapy.
• Galactosaminogalactan (GAG) secreted by Aspergillus species deposits on platelets, inducing activation.

Purpose of the Study:

• To investigate the interplay between platelets and complement in the presence of fungal GAG.
• To determine if GAG deposition on platelets triggers complement activation.
• To elucidate the role of this interaction in the pathogenesis of invasive aspergillosis.

Main Methods:

• Incubation of human platelets with culture supernatants from Aspergillus fumigatus and Aspergillus flavus.
• Analysis of GAG and complement C3 fragment deposition on platelets using immunofluorescence.
• Assessment of complement activation pathways, including the lectin pathway.
• Measurement of pro-inflammatory anaphylatoxins (C3a, C5a) and microparticle shedding.
• Evaluation of platelet viability and terminal complement complex (C5b-9) formation.

Main Results:

• Culture supernatants containing GAG induced deposition of complement C3 fragments on platelets.
• A mutant lacking GAG synthesis did not induce complement deposition, confirming GAG's role.
• GAG deposition directly triggered complement cascade activation via the lectin pathway.
• GAG-induced complement activation led to the release of pro-inflammatory anaphylatoxins (C3a, C5a) and platelet microparticles.
• Terminal complement complex (C5b-9) formed on platelets, correlating with reduced platelet viability.

Conclusions:

• Fungal GAG initiates a significant interplay between complement and platelets.
• This interaction promotes excessive inflammation, thrombocytopenia, and thrombosis in invasive aspergillosis.
• Targeting GAG-platelet-complement interactions may offer novel therapeutic strategies for invasive fungal infections.