Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response

外周血单个核细胞 干扰素 免疫学 转录组 表型 生物 单核细胞 基因 医学 基因表达 遗传学 体外 工程类 航空航天工程
作者
Camille de Cevins,Maxime Batignes,Laure Delage,Quentin Riller,Marine Luka,Anne Remaury,Boris Sorin,Tinhinane Fali,Cecile Masson,Benedicte Hoareau,Catherine Meunier,Melanie Parisot,Mohammed Zarhrate,Brieuc Pierre Perot,Victor Garcia,Francesco Carbone,Luc Canard,Charlotte Boussard,Etienne Crickx,Jean-Claude Guillemot,Marie-Louise Fremont,Benedicte Neven,Galina Boldina,Franck Auge,Alain Fischer,Michel Dider,Frédéric Rieux-Laucat,Mickaël M. Ménager
出处
期刊:Cold Spring Harbor Laboratory - medRxiv
标识
DOI:10.1101/2023.04.25.23288913
摘要

Abstract Gain-of-function mutations in STING1 , which encodes 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, which roles in the onset and severity of SAVI, remain 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 CD56 bright natural killer cells in SAVI patients, not observed in IFN-β-treated PBMC. Patients’ T cells present markers of early activation, associated with markers of senescence and apoptosis. Inferring cell-to-cell communication from scRNA-seq predicted monocytes as potential drivers of this T cell phenotype. Furthermore, scRNA-seq clustering identified a patient-specific subset of monocytes, expressing a strong integrated stress response (ISR), and high CCL3 , CCL4 and IL-6 . It also pinpointed to a patient with lower ISR, allowing us to identify a secondary mutation in PERK, 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 response. Altogether, these results provide a deeper understanding of SAVI at the cellular and molecular levels.
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