Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.
【저자키워드】 COVID-19, SARS-CoV2, autophagy, genetics, sarcoidosis, TANK Binding Kinase 1, mitophagy, 【초록키워드】 viral infection, Mutation, protocol, COVID-19 pandemic, Genetic, risk, host response, autophagy, viral infections, SARS-CoV2 infection, Rapamycin, Viral, Lungs, Patient, Clustering, Factors, pathway, target, infectious, retinoic acid, disease, sarcoidosis, function, Signaling, antiviral response, Hypothesis, Deleterious mutations, mTOR, Analysis, Genetic predisposition, genetic factors, mitochondrial, web server, Factor, Regulation, Exome, accumulation, healthy individuals, genetic defects, list, significant enrichment, hallmark, acid, inflammatory process, abnormality, pathogenic variant, genetic defect, mammalian, aggression, gateway, Affect, Course, shown, evaluate, involved, applied, characterized, functional, deleterious mutation, list of gene, 【제목키워드】 Familial, induced,