Microbial dysbiosis fuels STING-driven autoinflammation through cyclic dinucleotides

Area of Science:

• Immunology
• Microbiology
• Genetics

Background:

• Aberrant stimulator of interferon genes (STING) pathway activation causes autoinflammatory disorders like STING-associated vasculopathy with onset in infancy (SAVI).
• Mechanisms linking STING activation to SAVI pathology are not fully understood.
• SAVI involves systemic inflammation affecting blood vessels, skin, and lungs.

Purpose of the Study:

• To investigate the role of microbial dysbiosis and cyclic dinucleotides (CDNs) in SAVI pathogenesis.
• To explore STING pathway involvement in other autoimmune diseases like systemic lupus erythematosus (SLE).
• To identify potential biomarkers and therapeutic targets for STING-driven diseases.

Main Methods:

• Studied SAVI mice with N153S STING mutation, observing phenotypes including colitis and diarrhea.
• Analyzed gut microbiota composition and quantified microbial and host-derived CDNs in mice and patients.
• Administered antibiotics to SAVI mice to assess impact on inflammation.
• Correlated systemic CDN levels with disease biomarkers in SAVI, SLE, and rheumatoid arthritis (RA) patients.

Main Results:

• Diarrheal SAVI mice exhibited gut dysbiosis with reduced short-chain fatty acid producers and increased segmented filamentous bacteria.
• Elevated microbial and host CDNs were found in diarrheal SAVI mice and SAVI patients.
• Antibiotic treatment reduced inflammation in SAVI mice, confirming dysbiosis's role.
• In SLE patients, microbial CDNs correlated with type I interferon scores and anti-dsDNA antibodies, unlike in RA.

Conclusions:

• Microbial dysbiosis and elevated cyclic dinucleotides (CDNs) are key drivers of STING activation in SAVI.
• Systemic CDNs serve as potential biomarkers for STING-driven autoinflammatory and autoimmune diseases.
• Targeting cGAS or the microbiome based on CDN profiles offers personalized therapeutic strategies.