Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response
Camille de Cevins, Laure Delage, Maxime Batignes, Quentin Riller, Marine Luka, Anne Rémaury, Boris Sorin, Tinhinane Fali, Cécile Masson, Bénédicte Hoareau‐Coudert, Catherine Meunier, Mélanie Parisot, Mohammed Zarhrate, Brieuc P. Pérot, Víctor Paredes, Francesco Carbone, Lou Galliot, Béatrice Nal, Philippe Pierre, Luc Canard, Charlotte Boussard, Étienne Crickx, Jean‐Claude Guillemot, Brigitte Bader‐Meunier, Alexandre Bélot, Pierre Quartier, Marie‐Louise Frémond, Bénédicte Neven, Galina Boldina, Franck Augé, Fischer Alain, Michel Didier, Frédéric Rieux‐Laucat, Mickaël Ménager
Abstract
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.