ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/067/SRR23696967/SRR23696967.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/070/SRR23696970/SRR23696970.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/064/SRR23696964/SRR23696964.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/078/SRR23696978/SRR23696978.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/081/SRR23696981/SRR23696981.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/065/SRR23696965/SRR23696965.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/072/SRR23696972/SRR23696972.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/079/SRR23696979/SRR23696979.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/076/SRR23696976/SRR23696976.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/068/SRR23696968/SRR23696968.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/074/SRR23696974/SRR23696974.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/063/SRR23696963/SRR23696963.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/080/SRR23696980/SRR23696980.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/066/SRR23696966/SRR23696966.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/077/SRR23696977/SRR23696977.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/069/SRR23696969/SRR23696969.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/075/SRR23696975/SRR23696975.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/071/SRR23696971/SRR23696971.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/062/SRR23696962/SRR23696962.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/073/SRR23696973/SRR23696973.fastq.gzprimaryOK200GenomicsInstitut Imaginehttps://www.ebi.ac.uk/ena/browser/view/PRJNA940788Homo sapiensGain-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: 7 CTRL, 5 untreated SAVI patients, and 4 SAVI patients treated with a JAK-inhibitor (including 2 samples for the first patient)xref:PubMed:38118407ENAfalseSingle-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response IISingle-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response II2025-09-242024-01-02PRJNA940788GSE226598960638118407