Inborn errors of anti-viral interferon immunity in humans

Abstract

The three types of interferon (IFNs) are essential for immunity against at least some viruses in the mouse model of experimental infections, type I IFNs displaying the broadest and strongest anti-viral activity. Consistently, human genetic studies have shown that type II IFN is largely redundant for immunity against viruses in the course of natural infections. The precise contributions of human type I and III IFNs remain undefined. However, various inborn errors of anti-viral IFN immunity have been described, which can result in either broad or narrow immunological and viral phenotypes. The broad disorders impair the response to (STAT1, TYK2) or the production of at least type I and type III IFNs following multiple stimuli (NEMO), resulting in multiple viral infections at various sites, including herpes simplex encephalitis (HSE). The narrow disorders impair exclusively (TLR3) or mostly (UNC-93B, TRIF, TRAF3) the TLR3-dependent induction of type I and III IFNs, leading to HSE in apparently otherwise healthy individuals. These recent discoveries highlight the importance of human type I and III IFNs in protective immunity against viruses, including the TLR3-IFN pathway in protection against HSE.

Figure 1. Human deficiencies of types I and III IFNs

Following viral infection, immune receptors engage in the recognition of viral nucleic acids via the endosomal TLRs (TLR3, TLR7/8, TLR9), the cytosolic RLRs (RIGI, MDA5, LGP2), RNA-detecting DExD helicases (DDX1-DDX21-DHX36; DDX60, DHX9), NLRs (NOD2) or DNA receptors (DAI, IFI16, DDX41, RNA polymerase III, STING) (left panel). This in turn triggers various signaling pathways leading to the activation of the transcription factors NF-κB, IRF3 and IRF7 leading to the production of the antiviral IFNs, IFN-α/β and –λ. These IFNs are detected by their respective receptors: IFN-α/β by the heterodimers of IFN-αR1 and IFN-αR2, and IFN-λ by the heterodimers of IFN-λR1 and IL-10R2. This triggers the formation of the ISGF3 transcription factor complex that binds the IFN-stimulated response element (ISRE) resulting in the induction of numerous IFN stimulated genes (ISGs) initiating an antiviral response leading to the destruction of the virus (right panel). Mutations in NEMO, STAT1 or TYK2 are associated with multiple viral infections (in pale blue) while mutations in UNC93B1, TLR3, TRIF or TRAF3 are strictly associated with HSE. RNA molecules are shown in gray where as DNA is shown in black.