Molecular and cellular dissection of STING-Associated Vasculopathy with onset in Infancy -(SAVI) mediated intestinal inflammation

SAVI patients present with early-onset systemic inflammation and interstitial lung disease as a result of gain-of-function mutations in the STING expressing gene, Tmem173.Recent studies have demonstrated knock-in mouse models recapitulate the symptoms observed in SAVI-patients. Tmem173^+/N153smice present chronic lung inflammation and reduced lifespan as a result of ER-stress mediated T-cell death(1). Interestingly, IRF3 or IFNAR deficient Tmem173^+/N153s mice failed to suppress disease indicating SAVI is not a putative interferonopathy(2). In this study we demonstrate the Tmem173^+/N153smutation leads to progressive intestinal inflammation and propose constitutive activation of STING in the gut as the initial driver of SAVI-mediated disease. Tmem173^+/N153 mice exhibit severe signs of intestinal inflammation and tissue fibrosis.Whilst previous reports have highlighted T-cytopenia in the spleen and thymus, Tmem173^+/N153mice displayed an expansion and mis-localization of T-cell subsets in the intestinal layers. Antibiotic treatment completely alleviated intestinal inflammation, splenomegaly and morbidity in Tmem173^+/N153mice highlighting the microbiome as an essential contributing factor to disease.Most strikingly, antibiotic treatment did not alleviate lung inflammation indicating a dichotomy of disease phenotypes in Tmem173^+/N153mice. The present study characterizes a previously unknown phenotype associated with SAVI and highlights a new role for STING in the pathogenesis of intestinal inflammation.

1. Wu J, et al.(2019) STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death. The Journal of Experimental Medicine216(4):867-883.
2. Warner JD, et al.(2017) STING-associated vasculopathy develops independently of IRF3 in mice. The Journal of Experimental Medicine214(11):3279-3292.