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6.fastq.gzprimaryOK200GenomicsInstitut Imaginehttps://www.ebi.ac.uk/ena/browser/view/PRJNA940710Homo sapiensxref:PubMed:38118407Gain-of-function mutations in STING1, that codes for the Stimulator of Interferon Gene (STING), result in a severe autoinflammatory disease termed STING-associated vasculopathy with onset in infancy (SAVI). Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, and their role in the onset and severity of SAVI remains to be elucidated. To address this point, we compared a single-cell RNA sequencing (scRNA-seq) dataset of peripheral blood mononuclear cells (PBMCs) from SAVI patients to a dataset of healthy PBMCs treated with recombinant IFN-β. We revealed a loss of mucosal associated invariant T cells and CD56bright natural killer cells in SAVI patients, not replicated in IFN-β-treated PBMC. Patient T cells are in an activated state associated with senescence and apoptosis, dependent on type I IFNs. Inferring cell to cell communication, from scRNA-seq predicted monocytes as potential drivers of this T cell phenotype and was supported by plasma cytokines measurement, with high CCL3, CCL4 and IL-6. Furthermore, scRNA-seq clustering identified a patient-specific subset of monocytes, highly inflammatory and expressing a strong integrated stress response (ISR). It also pinpointed to a patient with lower ISR, allowing us to identify a secondary mutation in PERK, that was recently shown to be activated by STING to trigger the ISR. Finally, based on the identification of this patient-specific subset of monocytes and the exploration of IFN-β stimulated PBMCs from healthy donors, we developed a strategy to propose a transcriptomic signature specific of STING activation and independent of type I IFN. Altogether, these results provide a deeper understanding of SAVI at the cellular and molecular levels. Overall design: scRNA-seq on PBMCs (from healthy donors) treated with IFN-β at one of several timepoints (0h, 1h, 2h, 4h, 8h, 12h, 24h, 36h)ENAfalseSingle-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response ISingle-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response I2025-09-242024-01-02PRJNA940710GSE226572960638118407