Herpesviruses and the Type III Interferon System

Abstract

Type III interferons (IFNs) represent the most recently discovered group of IFNs. Together with type I IFNs (e.g. IFN-α/β), type III IFNs (IFN-λ) are produced as part of the innate immune response to virus infection, and elicit an anti-viral state by inducing expression of interferon stimulated genes (ISGs). It was initially thought that type I IFNs and type III IFNs perform largely redundant functions. However, it has become evident that type III IFNs particularly play a major role in antiviral protection of mucosal epithelial barriers, thereby serving an important role in the first-line defense against virus infection and invasion at contact areas with the outside world, versus the generally more broad, potent and systemic antiviral effects of type I IFNs. Herpesviruseses are large DNA viruses, which enter their host via mucosal surfaces and establish lifelong, latent infections. Despite the importance of mucosal epithelial cells in the pathogenesis of herpesviruses, our current knowledge on the interaction of herpesviruses with type III IFN is limited and largely restricted to studies on the alphaherpesvirus herpes simplex virus (HSV). This review summarizes the current understanding about the role of IFN-λ in the immune response against herpesvirus infections.

Keywords: Herpes simplex virus (HSV); Herpesvirus; Innate immunity; Type III interferon (IFN-λ).

Fig. 1

Pathway of Type III IFN induction and signaling, and interaction of type III IFN with HSV. HSV molecular patterns are recognized by TLR3 and TLR9 in the endosome and/or MDA5 in the cytoplasm, leading to the activation of the NF-κB, IRF3 and IRF7 transcription factors and their subsequent translocation to the nucleus where they stimulate IFN-λ gene transcription. Med23 and ANKRD1 are direct targets of IRF7 and IRF3 respectively and upregulate type III IFN expression. Secreted IFN-λ binds to a heterodimeric receptor composed of the IFNLR1 and IL-10RB receptor chains. IFN-λ binding leads to activation of JAK1/TYK2, which in turn leads to tyrosine phosphorylation of STAT1 and STAT2, resulting in the formation of STAT1–STAT2 heterodimers. Subsequently, STAT1–STAT2 heterodimers associate with IRF9, forming the ISGF3 complex, which then moves to the nucleus and triggers expression of interferon-stimulated genes (ISGs).