Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING

Area of Science:

• Immunology
• Microbiology
• Infectious Diseases

Background:

• The type I interferon (IFN) pathway is crucial in host defense against the fungal pathogen Candida albicans.
• The precise molecular mechanisms activating this pathway during C. albicans infection are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which the host innate immune system recognizes and responds to Candida albicans.
• To investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway in the host defense against C. albicans.

Main Methods:

• Mice lacking cGAS-STING pathway components were challenged intravenously with C. albicans.
• The activation of the cGAS-STING pathway was assessed by measuring interferon-stimulated genes, IFNβ production, and phosphorylation of key signaling molecules.
• Human monocytes with single nucleotide polymorphisms in cGAS and STING were used to evaluate inflammatory cytokine production.

Main Results:

• Mice deficient in cGAS-STING exhibited enhanced survival following C. albicans infection.
• Extracellular vesicles containing biofilm-associated C. albicans DNA were identified as triggers for the cGAS-STING pathway.
• Activation of type I IFNs by extracellular vesicles was independent of Dectin-1/Card9 and toll-like receptor 9.
• Genetic variations in cGAS and STING significantly impacted inflammatory cytokine responses in human monocytes.

Conclusions:

• The cGAS-STING pathway plays a critical role in the innate immune response to Candida albicans.
• Extracellular vesicle-encapsulated fungal DNA is a key activator of the cGAS-STING pathway, leading to type I IFN production.
• These findings offer novel insights into host-pathogen interactions and potential therapeutic targets for C. albicans infections.