A novel STING variant triggers endothelial toxicity and SAVI disease

Author:

Valeri Erika12ORCID,Breggion Sara2ORCID,Barzaghi Federica23ORCID,Abou Alezz Monah1ORCID,Crivicich Giovanni2ORCID,Pagani Isabel4ORCID,Forneris Federico56ORCID,Sartirana Claudia2ORCID,Costantini Matteo2ORCID,Costi Stefania7ORCID,Marino Achille7ORCID,Chiarotto Eleonora8ORCID,Colavito Davide8ORCID,Cimaz Rolando7,Merelli Ivan1ORCID,Vicenzi Elisa4ORCID,Aiuti Alessandro23ORCID,Kajaste-Rudnitski Anna51ORCID

Affiliation:

1. San Raffaele Telethon Institute for Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute 1 , Milan, Italy

2. Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute 2 , Milan, Italy

3. Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute 3 , Milan, Italy

4. Viral Pathogenesis and Biosafety Unit, IRCCS San Raffaele Scientific Institute 4 , Milan, Italy

5. University of Pavia 5 Department of Biology and Biotechnology, , Pavia, Italy

6. Fondazione IRCCS Policlinico San Matteo 6 , Pavia, Italy

7. Unit of Pediatric Rheumatology, ASST Gaetano Pini-CTO 7 , Milan, Italy

8. R&I Genetics Srl 8 , Padua, Italy

Abstract

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.

Funder

European Research Council

Telethon Foundation

Publisher

Rockefeller University Press

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