The consequences of SARS-CoV-2 exposure range from a lack of infection to lethal COVID-19. This immense inter-individual clinical variability is the key scientific and medical enigma in the field. While age and certain co-morbidities are known to influence disease outcome, these parameters do not explain all variation. In addition, there are other SARS-CoV-2 phenotypes of clinical importance: multisystem inflammatory syndrome in children and adults (MIS-C/A), and longCOVID. An important breakthrough to unravel the pathogenesis of COVID-19 came from our two Science papers that were recognized by Nature among the top 10 discoveries of 2020. We found that about 4% of patients with critical COVID-19 pneumonia had inborn errors of immunity (IEI) that impair TLR3- and IRF7-dependent type I interferon (IFN) immunity and at least 10% of the patients carried pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs. These findings pave the way for further studies of COVID-19 pneumonia and other SARS-CoV-2 infection phenotypes and form the basis of the present research proposal, UNDINE, which follows a "bed side to bench" and "bench to bed side" approach, with the following objectivies i) to decipher the genetic and immunological basis of the various SARS-CoV-2 disease manifestations, to identify individuals at increased risk of critical COVID-19, post-infectious immunological complications, and vaccine failure iii) to develop ready-to-use diagnostic tests for large-scale detection of auto-Abs to type I IFNs and propose novel preventive and therapeutic approaches, based on the pathogenesis of SARS-CoV-2 infection for translation into personalised medicine. To achieve these goals, our project will coordinate a European multidisciplinary and translational research effort relying on a strong and synergistic combination of assets, including unique cohorts from 11 EU countries and state-of-the art human genetic, immunological and virological expertises and technologies.