Abstract
Innate immunity and the actions of type I and III interferons (IFNs) are essential for protection from SARS-CoV-2 and COVID-19. Each is induced in response to infection and serves to restrict viral replication and spread while directing the polarization and modulation of the adaptive immune response. Owing to the distribution of their specific receptors, type I and III IFNs, respectively, impart systemic and local actions. Therapeutic IFN has been administered to combat COVID-19 but with differential outcomes when given early or late in infection. In this perspective, we sort out the role of innate immunity and complex actions of IFNs in the context of SARS-CoV-2 infection and COVID-19. We conclude that IFNs are a beneficial component of innate immunity that has mediated natural clearance of infection in over 700 million people. Therapeutic induction of innate immunity and use of IFN should be featured in strategies to treat acute SARS-CoV-2 infection in people at risk for severe COVID-19.