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Vertebrate cells are equipped with specialized receptors that sense the presence of viral nucleic acids and other conserved molecular signatures of infecting viruses. These sensing receptors are collectively called pattern recognition receptors (PRRs) and trigger the production of type I (α/β) interferons (IFNs). IFNs are secreted and establish a local and systemic antiviral state in responsive cells. Viruses, in turn, have evolved multiple strategies to escape the IFN system. They try to avoid PRR activation, inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Here, we summarize current knowledge in light of most recent findings on the intricate interactions of viruses with the IFN system. [ABSTRACT FROM AUTHOR]

Studies of the immunopathogenesis of systemic lupus erythematosus (SLE) have traditionally focused on the mechanisms of generation of the characteristic autoantibodies reactive with nucleic acid-containing intracellular particles and the contribution of autoantibody-autoantigen immune complexes to the inflammation and tissue damage that result in the clinical manifestations of lupus. The recent recognition of the central role of type I interferons (IFN) in this classic autoimmune disease has led to new understanding of the significant role of the innate immune system in the predisp to and amplification of autoimmunity and tissue damage. Ongoing studies are defining the genetic factors, immune stimuli, and molecular pathways that contribute to production of IFN and induction of its downstream targets in SLE. Investigations of lupus patients and murine lupus models suggest a primary role for type I IFNs in systemic autoimmunity and support the case for therapeutic inhibition of the IFN pathway in lupus and possibly other systemic autoimmune diseases. [ABSTRACT FROM AUTHOR]

Type I interferons (IFN-I) orchestrate numerous biological and cellular processes and are essential elements during host antiviral defense. After recognition of highly conserved virus signatures, a complex network of signaling events is rapidly initiated and leads to IFN-I synthesis. These cytokines directly induce a strong antiviral state and exert several immune-regulatory actions aimed at preventing virus spread. On the other hand, viruses evolved to evade or subvert the IFN-I system for their own benefit. In the present article, we review selective aspects of IFN-I induction and functions during several viral infections and discuss the beneficial and detrimental roles of IFN-I illustrated during lymphocytic choriomeningitis virus (LCMV) infection in its natural host, the mouse. [ABSTRACT FROM AUTHOR]

The type I interferons (IFN) are cytokines produced by mammalian cells in response to virus infection or other stressors. IFNs exert antiviral function by binding to the IFNα/β receptors on the cell surface, with the major effect of triggering the JAKSTAT signaling cascade and inducing the expression of interferon-stimulated genes. The resulting innate antiviral response is a first line of immune defense against virus infection. Recent studies demonstrate that many viruses, including hepatitis C virus, direct processes to control the host response to infection. We provide a review of the virus/host processes involved in IFN signaling and regulation of innate immune defenses. [ABSTRACT FROM AUTHOR]

The interferon system plays a profound role in determining the outcome of viral infection in mammals. Viruses induce the synthesis of interferon, which, in turn, blocks virus replication by inducing the expression of antiviral proteins encoded by interferon-stimulated genes. It is not widely appreciated that without the participation of interferon, many of the same genes can also be induced by a variety of virus-related agents, such as double-stranded RNA and viral proteins. In this chapter, we discuss different signaling pathways, activated by these agents, that lead to the induction of partially overlapping sets of genes, including the interferon-stimulated genes. We also review the biochemical and cellular properties of the protein products of a selected number of these genes including ISG56, ISG54, and ISG15. [ABSTRACT FROM AUTHOR]

The protein kinase R (PKR) is an intracellular sensor of stress, exemplified by viral infection. Double-stranded (ds) RNA produced during viral replication activates PKR, which in turn arrests protein synthesis by phosphorylating the α subunit of the translation initiation factor eIF2. As well as dsRNA, two additional ligands, PACT and heparin, directly activate the kinase. These mediate the response of PKR to additional indirect stimuli, including bacterial lipopolysaccharides, ceramide and polyanionic molecules. This responsiveness to multiple stimuli advocates a broader role for PKR as a signalling molecule for diverse physiological stresses. Appropriately, a number of other protein substrates have been reported for PKR. These substrates support additional roles for PKR in the regulation of transcription and signal transduction in infected cells, as well as uninfected but diseased tissues, such as in tumorigenesis and neurodegenerative diseases. Finally, PKR plays a role in normal cell differentiation in platelet-derived growth factor signalling and in osteoblast-mediated calcification. [ABSTRACT FROM AUTHOR]

Production of type I IFN is the key response to viral infection. Since the discovery of type I IFNs in 1957, long double-stranded RNA formed during replication of many viruses was thought to be responsible for type I IFN induction, and for decades double-stranded RNA-activated protein kinase (PKR) was thought to be the receptor. Recently, this picture has dramatically changed. It now became evident that not PKR but two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, and two cytosolic helicases, RIG-I and MDA-5, are responsible for the majority of type I IFNs induced upon recognition of viral nucleic acids. In this review, we focus on the molecular mechanisms by which those innate immune receptors detect viral infection. Based on the recent progress in the field, we now know that TLR7, TLR9, and RIG-I do not require long double-stranded RNA for type I IFN induction. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are crucially important in the sensing of viral infections and viral nucleic acids. TLR triggering leads to the induction of specific intracellular signaling cascades that result in the activation of two major families of transcription factors; the IFN-regulatory factors (IRFs) and nuclear factor-kappa B (NF-κB). IRFs and NF-κB work together to trigger the production of type I interferons (IFNα/β) or inflammatory cytokines leading to the maturation of dendritic cells and the establishment of antiviral immunity. This review will focus on the most recent findings relating to the regulation of IRF activity by TLRs, highlighting the increasing complexity of TLR-mediated signaling pathways. [ABSTRACT FROM AUTHOR]

The recognition of viral nucleic acids with pattern recognition receptors (PRRs) is the first step in inducing the innate immune system. Type I interferons (IFNs), central mediators in antiviral innate immunity, along with other cytokines and chemokines, disrupt virus replication. Recent studies indicated at least two distinct pathways for the induction of type I IFN by viral infection. Toll-like receptors (TLRs) are extracellular or endosomal PRRs for microbial pathogens, whereas retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are novel intracellular PRRs for the viral dsRNA. In this review, we describe the distinct mechanisms inducing type I IFNs through TLRs and RIG-I/MDA5 pathways. [ABSTRACT FROM AUTHOR]

Celebrations are certainly in order for the 50th anniversary of the Isaacs/Lindenmann discovery of interferon as a secreted substance of probable cellular origin that conferred resistance to at least four viruses of distinctly different character—influenza, Sendai, Newcastle's disease, and vaccinia. Personal pride, excusable, I hope, leads me to recall also that following the trail of how interferon works its magic led 15 years ago this year to the discovery of the STATs and their activation by the Jak kinases. These later findings were stimulated by and in turn further stimulated an ever deepening interest in how transcription figured in changing cell behavior. Here are presented some further reflections on these topics. [ABSTRACT FROM AUTHOR]

All type I IFNs act through a single cell surface receptor composed of the IFNAR1 and IFNAR2 subunits and two associated cytoplasmic tyrosine kinases of the Janus family, Tyk2 and Jak1. A central issue in type I IFN biology is to understand how a multitude of subtypes can generate similar signaling outputs but also govern specific cellular responses. This review summarizes results from the last decade that contributed to our current state of knowledge of IFN-receptor complex structure and assembly. [ABSTRACT FROM AUTHOR]

Type II interferon-γ (IFN-γ) is a pleiotropic cytokine that regulates many different cellular functions. The major signaling pathway activated by IFN-γ involves sequential phosphorylation of the tyrosine residues of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins, providing the primary mechanism through which gene expression is induced. However, recent work has revealed that the responses are complex, as shown by the activation of kinases in addition to JAKs, differential patterns of activation of STAT1, STAT3, and STAT5 in different cells, and activation of transcription factors other than STATs. This complexity is used to regulate biological functions differentially in a cell type-specific manner, by activating different specific signals and patterns of gene expression. [ABSTRACT FROM AUTHOR]

Interferon-gamma (IFN-γ) is a key immunoregulatory protein that plays a major role in the host innate and adaptive immune response. Also known as type II interferon, IFN-γ is a single-copy gene whose expression is regulated at multiple levels by the host. Transcription control is regulated through epigenetic mechanisms as well as the accessibility of chromatin and the binding of activating and inhibitory proteins to promoter and enhancer elements. Post-transcriptional control is mediated through mRNA localization and mRNA stability while post-translational control occurs through the activation of protein kinase R by the 5 portion of the mRNA, protein folding within the endoplasmic reticulum and the possible interaction of the mRNA with microRNAs. The biological effects of IFN-γ are widespread, as almost every cell type is altered upon interaction with this protein. Thus it has become very apparent that IFN-γ is a multipotent cytokine whose regulation and effects are complex and essential to host survival. [ABSTRACT FROM AUTHOR]

Since the discovery of interferon 50 years ago, the understanding of the mechanism of the virus-mediated induction of type I IFN and its function has been under intensive investigation. Remarkable progress has been made in recent years both in the identification of cellular receptors detecting the viral infection and in the understanding the signaling pathways resulting in the induction of interferon and interferon-induced genes. In this review of type I interferon, we aim to summarize not only the historical site of the interferon induction and its antiviral function, but also the complexity of the signals that lead to activation of expression of interferon genes and the expanding repertoire of this multifunctional protein. [ABSTRACT FROM AUTHOR]

As we approach the 50th anniversary of the publications describing the discovery of interferon, it is appropriate to look back at some of the trials and tribulations marking the early days of interferon research. This brief chapter, drawn largely from the author's own experiences, relates how progress was achieved in some key areas of interferon research in the 1960s and 1970s despite the lack of analytical tools that had become available only after the successful cloning of interferon genes. One of the topics discussed concerns the evolution of the idea that interferon synthesis is controlled both at transcriptional and posttranscriptional levels. I also recount some of the early work that led to the identification of IFN-α and IFN-β as the two major type I interferon species. [ABSTRACT FROM AUTHOR]

Interferon alpha (IFN-α) was approved by the US Food and Drug Administration on June 5, 1986 and paved the way for development of many other cytokines and growth factors. Nevertheless, we have barely touched the surface of understanding the multitude of human IFNs. This paper reviews the history of the purification of human leukocyte IFN, the cloning of the IFN-αs, and the current state of knowledge of human interferon alpha genes and proteins. [ABSTRACT FROM AUTHOR]

The collaboration between Alick Isaacs and myself started in the summer of 1956. Our initial project was to show, by electron microscopy, that interference between inactivated influenza virus and live virus involved the transfer of material from the interfering virus to the host cell. This approach failed for technical reasons. However, in the course of this work it appeared that more interfering activity remained in the system than we were entitled to expect. One possible explanation was that a substance, not identical with the initial interfering virus, was being generated. Subsequent experiments, aimed at checking this hypothesis, led to the description of interferon. [ABSTRACT FROM AUTHOR]