ena-STUDY-WASHINGTON UNIVERSITY SCHOOL OF MEDICINE-06-01-2021-19:26:20:082-422
Transferrable protection by gut microbes against STING-associated lung disease
STING modulates immunity in response to bacterial and endogenous cyclic dinucleotides (CDNs). Humans and mice with gain-of-function mutations in STING develop a syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is associated with vasculopathy and lung disease. We hypothesized that hyperresponsiveness of STING gain-of-function to bacterial CDNs might explain autoimmune lung disease in SAVI mice. Depletion of gut microbes with oral antibiotics (VNA; vancomycin, neomycin, ampicillin) nearly eliminates lung disease in SAVI mice and diminishes cytokine production, suggesting that gut microbes promote STING-associated autoimmunity. However, we demonstrate that germ-free SAVI mice develop severe lung disease, and that transferring gut microbiota from VNA antibiotics-treated mice to germ-free animals eliminates lung disease. Depletion of anaerobes with metronidazole eliminates the protective effect of other antibiotics, and recolonization with the anaerobe Bacteroides thetaiotaomicron prevents lung disease in SAVI mice, confirming a protective role of metronidazole-sensitive microbes in a model of SAVI.
STING modulates immunity in response to bacterial and endogenous cyclic dinucleotides (CDNs). Humans and mice with gain-of-function mutations in STING develop a syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is associated with vasculopathy and lung disease. We hypothesized that hyperresponsiveness of STING gain-of-function to bacterial CDNs might explain autoimmune lung disease in SAVI mice. Depletion of gut microbes with oral antibiotics (VNA; vancomycin, neomycin, ampicillin) nearly eliminates lung disease in SAVI mice and diminishes cytokine production, suggesting that gut microbes promote STING-associated autoimmunity. However, we demonstrate that germ-free SAVI mice develop severe lung disease, and that transferring gut microbiota from VNA antibiotics-treated mice to germ-free animals eliminates lung disease. Depletion of anaerobes with metronidazole eliminates the protective effect of other antibiotics, and recolonization with the anaerobe Bacteroides thetaiotaomicron prevents lung disease in SAVI mice, confirming a protective role of metronidazole-sensitive microbes in a model of SAVI.