SPECIAL SEMINAR - Dr. Mickaël MENAGER - UMR Inserm 1163

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

Dr. Mickaël MENAGER

PhD – HDR – INSERM CRCN

UMR Inserm 1163

Inflammatory Responses and Transcritpomic Networks in Disease

Institut Imagine - PARIS

Abstract

In this work, performed in collaboration between my team and the team of Frédéric Rieux-Laucat, we explored, through gene expression performed at the single-cell level combined with cytokines/chemokines expression, the peripheral blood mononuclear cells (PBMCs) and plasma of patients with gain-of-function mutations in stimulator of interferon gene 1 (STING1), resulting in STING-associated vasculopathy with onset in infancy (SAVI), a rare monogenic severe autoinflammatory diseases. Patients are suffering from severe pulmonary and cutaneous manifestations and this pathology is characterized at the molecular level by an excessive and uncontrolled production of type-I interferon. Here, we identified, thanks to a very fine-tuned analysis performed at the single-cell level, a population of monocytes associated with the disease and presenting an upregulation of the unfolded protein response (UPR), and expressing high CCL3, CCL4 and IL-6. Those disease related monocytes are predicted to lead to T cell early activation, subsequently leading to their senescence and apoptosis. From those analyses, we also characterized a signature of 21 genes specific of STING activation, independently of type-I IFN response and identified in one of the patient, a variant in the gene EIF2AK3, encoding for the protein PERK, master regulator of the UPR and integrated stress response. Altogether, our work paves the way towards a better comprehension of the physiopathology of SAVI patients and provide new potential biomarkers for a better stratification, at the molecular level, of patients with type-I interferonopathies, which could be proven to be quite useful in clinics for diagnosis in rare and more common autoinflammatory diseases.