tetano
Editor, Senior Moderator
Cells
. 2021 Aug 5;10(8):1995.
doi: 10.3390/cells10081995.
Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses
Yves Pacheco[SUP] 1 [/SUP], Dominique Valeyre[SUP] 2 [/SUP], Thomas El Jammal[SUP] 1 3 [/SUP], Maxime Vallee[SUP] 4 [/SUP], Fabien Chevalier[SUP] 1 [/SUP], Jérôme Lamartine[SUP] 1 [/SUP], Dominique Sigaudo-Roussel[SUP] 1 [/SUP], Bernard Verrier[SUP] 1 [/SUP], Dominique Israel-Biet[SUP] 5 [/SUP], Nathalie Freymond[SUP] 6 [/SUP], Vincent Cottin[SUP] 7 [/SUP], Alain Calender[SUP] 1 8 [/SUP]
Affiliations
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.
Keywords: COVID-19; SARS-CoV2; TANK Binding Kinase 1; autophagy; genetics; mitophagy; sarcoidosis.
. 2021 Aug 5;10(8):1995.
doi: 10.3390/cells10081995.
Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses
Yves Pacheco[SUP] 1 [/SUP], Dominique Valeyre[SUP] 2 [/SUP], Thomas El Jammal[SUP] 1 3 [/SUP], Maxime Vallee[SUP] 4 [/SUP], Fabien Chevalier[SUP] 1 [/SUP], Jérôme Lamartine[SUP] 1 [/SUP], Dominique Sigaudo-Roussel[SUP] 1 [/SUP], Bernard Verrier[SUP] 1 [/SUP], Dominique Israel-Biet[SUP] 5 [/SUP], Nathalie Freymond[SUP] 6 [/SUP], Vincent Cottin[SUP] 7 [/SUP], Alain Calender[SUP] 1 8 [/SUP]
Affiliations
- PMID: 34440765
- DOI: 10.3390/cells10081995
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.
Keywords: COVID-19; SARS-CoV2; TANK Binding Kinase 1; autophagy; genetics; mitophagy; sarcoidosis.