From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

The immense interindividual clinical variability during any infection is a long-standing enigma. Inborn errors of IFN-g and IFN-a/f3 immunity underlying rare infections with weakly virulent mycobacteria and seasonal influenza virus have inspired studies of two common infections: tuberculosis and COVID-19. A TYK2 genotype impairing IFN-g production accounts for about 1% of tuberculosis cases, and autoantibodies neutralizing IFN-a/f3 account for about 15% of critical COVID-19 cases. The discovery of inborn errors and mechanisms underlying rare infec-tions drove the identification of common monogenic or autoimmune determinants of related common infections. This "rare-to-common"genetic and mechanistic approach to infectious diseases may be of heuristic value.