Recherche Fondamentale (basic research) - Identification des défauts monogéniques de l'immunité responsables des formes sévères d'infections à SARS-CoV-2 chez les patients précédemment en bonne santé Search for inborn errors of immunity underlying severe SARS-CoV-2 infections in previously healthy individuals

The major role of human genetic variability in immunity to infection is now well established, in particular for viral infections. We have identified a number of monogenic inborn errors of immunity (IEIs) underlying life-threatening viral diseases, such as herpes simplex virus encephalitis, fulminant viral hepatitis, severe cytomegalovirus primary infection, and severe influenza pneumonitis. In December 2019, a pneumonia due to a novel coronavirus (SARS-CoV-2) emerged in the city of Wuhan, China, and quickly spread world-wide with an increasing number of cases and deaths. In populations naive to this new pathogen, there has been stunning inter-individual variability among infected individuals, ranging from asymptomatic infection to lethal coronavirus infectious disease-19 (COVID-19). Two groups are at high risk of severe disease: elderly people (>70 years) and patients with a pre-existing condition (including but not limited to cardiovascular and pulmonary diseases, diabetes and obesity, liver or kidney dysfunctions, and overt immunodeficiency). Among patients under 40 years, the case-fatality ratio is < 0.2%. The proportions of severe cases are probably even smaller among all infected individuals (currently unknown in the absence of serological data). Only a small proportion of otherwise healthy, young people therefore fail to control SARS-CoV-2 infection. In this context, we hypothesize that life-threatening COVID-19 in previously healthy individuals younger than 50 years can be caused by IEIs. To test this hypothesis, our project will tackle three specific aims: 1) to recruit otherwise healthy young patients with severe COVID-19 in France, and in three countries from Latin America, Mexico, Colombia, and Brazil (and their family members when available); 2) to search for candidate disease-causing variants using a cutting-edge strategy developed in our laboratory to analyze whole-exome sequencing data of patients and controls (including asymptomatic infected subjects); and 3) to perform in-depth functional studies to characterize the products of the candidate variants biochemically, and to analyze the corresponding patients' cells immunologically. Our highly innovative project is feasible, as it is based on a unique collection of patients, with stringent inclusion criteria, the longstanding collaboration of the French partner with the four Latin America partners, and benefits from the unique expertise of the French laboratory in the discovery of IEI underlying severe infectious diseases. The immunological implications of our project are considerable, as we will discover the pathogenesis of severe, unexplained COVID-19, thereby revealing essential circuits involved in host defense against SARS-CoV-2. Our project should also facilitate genetic diagnosis and counseling, including specific preventive measures, while paving the way for the development of novel preventive and therapeutic strategies including anti-viral drugs (e.g. aimed at restoring a deficient immunity) and vaccines (e.g. aimed at boosting certain immunological pathways).