A novel STING variant triggers endothelial toxicity and SAVI disease

Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease and contribute to a better understanding of how aberrant STING activation can cause pathology. Overall design: To study the phenotype of blood cells carrying a novel identified STING variant (F269S) causing SAVI disease, we interrogated the transcriptome of different bone marrow (BM)-derived mononuclear cell (MNC) subsets performing single-cell RNA-Seq (scRNASeq). SAVI patient cells were compared to pediatric healthy donor control cells.