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

Camille de Cevins (1) , Laure Delage (1) , Maxime Batignes (1) , Quentin Riller (1) , Marine Luka (1) , Anne Remaury (2) , Boris Sorin (1) , Tinhinane Fali (1) , Cécile Masson (1) , Bénédicte Hoareau (3) , Catherine Meunier (3) , Mélanie Parisot (4) , Mohammed Zarhrate (4) , Brieuc P Pérot (1) , Víctor García-Paredes (1) , Francesco Carbone (1) , Lou Galliot (5) , Béatrice Nal (5) , Philippe Pierre (5) , Luc Canard (2) , Charlotte Boussard (1) , Etienne Crickx (1) , Jean-Claude Guillemot (2) , Brigitte Bader-Meunier (6) , Alexandre Bélot (7) , Pierre Quartier (6) , Marie-Louise Frémond (1) , Bénédicte Neven (1, 6) , Galina Boldina (8) , Franck Augé (8) , Fischer Alain (1) , Michel Didier (2) , Frédéric Rieux-Laucat (1) , Mickaël M Ménager (1)

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 Sanofi Aventis R&D [Chilly-Mazarin]
3 PASS-CYPS - Cytométrie Pitié-Salpêtrière
4 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
5 CIML - Centre d'Immunologie de Marseille - Luminy
6 Hôpital Necker - Enfants Malades [AP-HP]
7 CIRI - Centre International de Recherche en Infectiologie
8 Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics, Omics Data Science

Gain-of-function mutations in stimulator of interferon gene 1 (STING1) result in STING-associated vasculopathy with onset in infancy (SAVI), a severe autoinflammatory disease. 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 have roles in the onset and severity of SAVI and remain to be elucidated. To this end, we performed a multi-omics comparative analysis of peripheral blood mononuclear cells (PBMCs) and plasma from SAVI patients and healthy controls, combined with a dataset of healthy PBMCs treated with IFN-β. Our data reveal a subset of disease-associated monocyte, expressing elevated CCL3, CCL4, and IL-6, as well as a strong integrated stress response, which we suggest is the result of direct PERK activation by STING. Cell-to-cell communication inference indicates that these monocytes lead to T cell early activation, resulting in their senescence and apoptosis. Last, we propose a transcriptomic signature of STING activation, independent of type I IFN response.

Keywords: type I interferon; SAVI; STING; unfolded protein response; integrated stress response; scRNA-seq

Domains: Life Sciences [q-bio]

Camille de Cevins, Laure Delage, Maxime Batignes, Quentin Riller, Marine Luka, et al.. Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response. Cell Reports Medicine, 2023, 4 (12), pp.101333. ⟨10.1016/j.xcrm.2023.101333⟩. ⟨hal-04546943⟩