Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

Abstract

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.

Sarcoidosis following SARS‐CoV‐2 infection: Cause or consequence?

“… 3 Furthermore, two recently published studies have demonstrated, by evaluating the genes involved in the pathogenesis of sarcoidosis and the interactome of the SARS‐CoV‐2 host cell, that the two diseases may involve common cellular pathways in the regulation of autophagy and mitophagy, specifically TBK1 and BRD4. 4 , 5 …”

“…3 Furthermore, two recently published studies have demonstrated, by evaluating the genes involved in the pathogenesis of sarcoidosis and the interactome of the SARS-CoV-2 host cell, that the two diseases may involve common cellular pathways in the regulation of autophagy and mitophagy, specifically TBK1 and BRD4. 4,5 Also noteworthy is the diagnostic interpretation of the cutaneous lesions at the time of SARS-CoV-2 infection. In this case, these lesions were initially attributed to the SARS-CoV-2 infection.…”

“…Celada et al performed molecular, genetic and immunological studies on patients with sarcoidosis, proving the roles of a number of infectious agents in the aetiology of sarcoidosis 3 . Furthermore, two recently published studies have demonstrated, by evaluating the genes involved in the pathogenesis of sarcoidosis and the interactome of the SARS‐CoV‐2 host cell, that the two diseases may involve common cellular pathways in the regulation of autophagy and mitophagy, specifically TBK1 and BRD4 4,5 …”

In silico Analysis of SARS-CoV-2 ORF8-Binding Proteins Reveals the Involvement of ORF8 in Acquired-Immune and Innate-Immune Systems

“…Although the mechanism is unclear, we postulate that ORF8 partly contributes to COVID-19 pathogenesis via this system. Moreover, some proteins in Class 1, including IL17RA, growth differentiation factor 15, FK506-binding protein 10, and PLAT, are associated with sarcoidosis pathogenesis ( 22 ). Indeed, it is known that ORF8 plays a role in COVID-19 pathogenesis, and a variant with its absence leads to milder illness ( 6 ).…”

Sarcoidosis developing after COVID‐19: A case report

“… 9 , 10 Several studies have demonstrated that COVID‐19 might share common features with sarcoidosis involving common mechanistic cellular pathways around the regulation of autophagy and mitophagy. 11 , 12 …”