Transferrable protection by gut microbes against STING-associated lung disease

Derek J. Platt, Dylan Lawrence, Rachel Rodgers, Lawrence Schriefer, Wei Qian, Cathrine A. Miner, Amber M. Menos, Elizabeth A. Kennedy, Stefan T. Peterson, W. Alexander Stinson, Megan Baldridge, Jonathan J. Miner

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

STING modulates immunity by responding to bacterial and endogenous cyclic dinucleotides (CDNs). Humans and mice with STING gain-of-function mutations develop a syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is characterized by inflammatory or fibrosing lung disease. We hypothesized that hyperresponsiveness of gain-of-function STING to bacterial CDNs might explain autoinflammatory lung disease in SAVI mice. We report that depletion of gut microbes with oral antibiotics (vancomycin, neomycin, and ampicillin [VNA]) nearly eliminates lung disease in SAVI mice, implying that gut microbes might promote STING-associated autoinflammation. However, we show that germ-free SAVI mice still develop severe autoinflammatory disease and that transferring gut microbiota from antibiotics-treated mice to germ-free animals eliminates lung inflammation. Depletion of anaerobes with metronidazole abolishes the protective effect of the VNA antibiotics cocktail, and recolonization with the metronidazole-sensitive anaerobe Bacteroides thetaiotaomicron prevents disease, confirming a protective role of a metronidazole-sensitive microbe in a model of SAVI.

Original languageEnglish
Article number109113
JournalCell Reports
Volume35
Issue number6
DOIs
StatePublished - May 11 2021

Keywords

  • Bacteroides
  • SAVI
  • STING
  • autoimmunity
  • cGAMP
  • cGAS
  • lung disease
  • microbiome
  • microbiota

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