Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

Abstract

Type I IFNs are so-named because they interfere with viral infection in vertebrate cells. The study of cellular responses to type I IFNs led to the discovery of the JAK-STAT signaling pathway, which also governs the response to other cytokine families. We review here the outcome of viral infections in mice and humans with engineered and inborn deficiencies, respectively, of (i) IFNAR1 or IFNAR2, selectively disrupting responses to type I IFNs, (ii) STAT1, STAT2, and IRF9, also impairing cellular responses to type II (for STAT1) and/or III (for STAT1, STAT2, IRF9) IFNs, and (iii) JAK1 and TYK2, also impairing cellular responses to cytokines other than IFNs. A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated. Mouse type I IFNs are essential for protection against a broad range of viruses in experimental conditions. These findings suggest that various type I IFN-independent mechanisms of human cell-intrinsic immunity to viruses have yet to be discovered.

Figure 1

Overview of Type I, Type II and Type III Signaling Pathways. Upon binding to their respective receptors, the JAK-STAT signaling pathways are activated that lead ultimately to induction and transcription of ISGs, resulting in the induction of antiviral responses. In humans, IFNAR1 and IFNAR2 deficiency predispose to disease following LAV vaccine, but also to Herpes Simplex Encephalitis and severe COVID-19. AR STAT2 deficiency is characterized by a broader phenotype with susceptibility to LAV but also to various other viruses. AR complete STAT1 deficiency presents with the most severe phenotype, including life-threatening viral infections, but also life-threatening mycobacterial infections. TYK2 deficiency is similar but with a somewhat milder viral phenotype. No humans with complete JAK1 deficiency are described until now. In mice, there is broad viral susceptibility with STAT1−/− more severe than Ifnar1−/− and Ifnaar2−/− and STAT2−/− mice, and these more severe than Tyk2−/− and Irf9−/− at least for the viruses and the models tested. The width of the blue bar indicates the extent of viral susceptibility.