Genetic Predisposition to Severe Forms of COVID-19 (SARS-CoV2 Infection) in Patients Without Comorbidities

The main objective of this part of the project is to identify the germline genetic factors which discriminate the benign and severe forms of SARS-CoV2 (CoVID-19) infection in the context of the ongoing SARS-CoV2 (HCOVID-19) epidemic. The scientific arguments of the project are described in APPENDIX. We hypothesize that pathogenic variants in genes coding for crucial factors involved in the HOST PATHOGEN interaction could explain the susceptibility of some patients to severe disease, even in the absence of comorbidities. The challenge is to identify those of the genetic factors who may be related respiratory distress and potentially further death. Based on our previous experience in sarcoidosis, a multifactorial disease predisposing to opportunistic infections, we will focus particularly the regulation of apoptosis and autophagy, immune response to viral infection, and endoplasmic reticulum stress response (ER STRESS) which is closely linked to apoptosis. Genetic defects in such pathways may decrease the clearance of viral particles and induces the progressive invasion by SARS-CoV2 and destruction of lung parenchyma. Our strategy will be similar to that described in our previous studies on sarcoidosis, recently published. We will combine a comparative genotype analysis by WHOLE EXOME SEQUENCING (WES) of benign and severe forms of SARS-CoV2 infection through clinical subgroups defined by the infectious diseases experts and a bioinformatics analysis of the functional networks identified by the panel of genes sharing pathogenic variants and discriminating the severe forms of the diseases. WES data will be carefully analyzed and related to all the intracellular physiological process and also the functional pathways involved in host-pathogen interaction: viral targets on the cell surface and downstream signaling, viral genomic RNA replication and translation, production and release of new viral particles. Finally, our main objectives are the definition of a gene panel more specifically related to severe forms of infection and the characterization of defective pathways involved in pejorative forms of SARS-COv2 disease in order to identify putative therapeutic targets.