Type I IFN family members: similarity, differences and interaction

Abstract

Interferons (IFN) are key cytokines with multifaceted antiviral and cell-modulatory properties. Three distinct types of IFN are recognized (I-III) based on structural features, receptor usage, cellular source and biological activities. The action of IFNs is mediated by a complex, partially overlapping, transcriptional program initiated by the interaction with specific receptors. Genetic diversity, with polymorphisms and mutations, can modulate the extent of IFN responses and the susceptibility to infections. Almost all viruses developed mechanisms to subvert the IFN response, involving both IFN induction and effector mechanisms. Interactions between IFN types may occur, for both antiviral and cell-modulatory effects, in a complex interplay, involving both synergistic and antagonistic effects. Interferon-associated diseases, not related to virus infections may occur, some of them frequently observed in IFN-treated patients. On the whole, IFNs are pleiotropic biologic response modifiers, that, upon activation of thousands genes, induce a broad spectrum of activities, regulating cell cycle, differentiation, plasma membrane molecules, release of mediators, etc., that can be relevant for cell proliferation, innate and adaptive immunity, hematopoiesis, angiogenesis and other body functions.

Keywords: Anti-interferon strategies; Interferon genes and receptors; Interferon types I–III; Interferon–interferon interactions.

Fig. 1

A simplified overview of the IFN signaling pathways counteracted by viruses. (a) After the viral entry and uncoating, the detection of viral genome by cytoplasmic or endosomal sensors is prevented by many viral strategies which, on the whole, target the nuclear translocation of transcription factors (NF-κB, IRF-3, AP-1); other strategies include the block of upstream mediators such as MDA-5 or TLRs. (b) Mechanisms that target the IFN cellular response through the block of JAK-STAT signaling pathway: degradation or cytoplasmic sequestration of STAT proteins by reduction of phosphorylation. See text for details. Abbreviations: ADAR1, adenosine deaminase acting on RNA 1; AP-1, activator protein 1; E6 early protein 6 (HPV); GAS, interferonγ-activated sequence; ISRE, interferon stimulated response element; IRF, interferon regulatory factor; JAK, janus kinase; MDA-5, melanoma differentiation-associated protein 5; NF-κB, NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; NS-1, non structural protein 1 (Influenza types A, B, C); PKR, protein kinase R; RIG-1, retinoic acid inducible gene 1; RSV, respiratory syncytial virus; SOCS, suppressor of cytokine signaling; STAT, signal transducers and activators of transcription; TYK-2, tyrosine kinase 2, TLR, toll-like receptors.