Unlocking life-threatening COVID-19 through two types of inborn errors of type I IFNs

Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying a few severe viral illnesses. Autoantibodies neutralizing type I IFNs due to rare inborn errors of autoimmune regulator (AIRE)-driven T cell tolerance were discovered in 2006, but not initially linked to any viral disease. These two lines of clinical investigation converged in 2020, with the discovery that inherited and/or autoimmune deficiencies of type I IFN immunity accounted for approximately 15%-20% of cases of critical COVID-19 pneumonia in unvaccinated individuals. Thus, insufficient type I IFN immunity at the onset of SARS-CoV-2 infection may be a general determinant of life-threatening COVID-19. These findings illustrate the unpredictable, but considerable, contribution of the study of rare human genetic diseases to basic biology and public health.

Automated summary

Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying severe viral illnesses. In 2006, autoantibodies neutralizing type I IFNs due to rare inborn errors of autoimmune regulator (AIRE)-driven T cell tolerance were discovered, but not initially linked to any viral disease. These two lines of clinical investigation converged in 2020, revealing that deficiencies of type I IFN immunity accounted for a significant percentage of critical COVID-19 cases in unvaccinated individuals.