Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.
Hannah Brown HardingGeneva N KwakuChristopher M ReardonNida S KhanDaniel Zamith-MirandaRobert ZarnowskiJenny M TamCollins K BohaenLauren RicheyKenta MosallanejadArianne J CrossenJennifer L ReedyRebecca A WardDiego A Vargas-BlancoKyle J BashamRoby P BhattacharyyaJeniel E NettMichael K MansourFrank L van de VeerdonkVinod KumarJonathan C KaganDavid R AndesJoshua Daniel NosanchukJatin M VyasPublished in: Nature microbiology (2024)
The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown. Here we reveal that mice lacking cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway components had improved survival following an intravenous challenge by C. albicans. Biofilm-associated C. albicans DNA packaged in extracellular vesicles triggers the cGAS-STING pathway as determined by induction of interferon-stimulated genes, IFNβ production, and phosphorylation of IFN regulatory factor 3 and TANK-binding kinase 1. Extracellular vesicle-induced activation of type I IFNs was independent of the Dectin-1/Card9 pathway and did not require toll-like receptor 9. Single nucleotide polymorphisms in cGAS and STING potently altered inflammatory cytokine production in human monocytes challenged by C. albicans. These studies provide insights into the early innate immune response induced by a clinically significant fungal pathogen.
Keyphrases
- candida albicans
- immune response
- dendritic cells
- biofilm formation
- toll like receptor
- endothelial cells
- genome wide
- oxidative stress
- protein kinase
- adipose tissue
- gene expression
- metabolic syndrome
- escherichia coli
- low dose
- transcription factor
- cystic fibrosis
- staphylococcus aureus
- binding protein
- cell wall
- insulin resistance
- bioinformatics analysis
- genome wide analysis