Type I and type III interferons: From basic biology and genetics to clinical development for COVID-19 and beyond

Type I and type III interferons (IFNs) constitute a key antiviral defense systems of the body, inducing viral resistance to cells and mediating diverse innate and adaptive immune functions. Defective type I and type III IFN responses have recently emerged as the 'Achilles heel' in COVID-19, with such patients developing severe disease and exhibiting a high risk for critical pneumonia and death. Here, we review the biology of type I and type III IFNs, their similarities and important functional differences, and their roles in SARS-CoV-2 infection. We also appraise the various mechanisms proposed to drive defective IFN responses in COVID-19 with particular emphasis to the ability of SARS-CoV-2 to suppress IFN production and activities, the genetic factors involved and the presence of autoantibodies neutralizing IFNs and accounting for a large proportion of individuals with severe COVID-19. Finally, we discuss the long history of the type I IFN therapeutics for the treatment of viral diseases, cancer and multiple sclerosis, the various efforts to use them in respiratory infections, and the newly emerging type III IFN therapeutics, with emphasis to the more recent studies on COVID-19 and their potential use as broad spectrum antivirals for future epidemics or pandemics.