Interferons (IFNs) were first discovered in 1957 by Isaacs and Lindenman as an activity which was inducible by heat killed influenza virus in chick chorioallantoic membranes and could potently inhibit infection of fresh chick chorioallantoic membranes with live virus. It is composed of a family of distinct, acid stabile proteins which are highly similar in amino acid sequence and structure.
Persons with disorders of the interferon system are more susceptible to viral and bacterial diseases. Those with interferon production deficiencies are more susceptible to diseases caused by viruses such as HBV. Chronic hepatitis B virus infection acquired in later life is also associated with a defect in interferon production. Patients with defects in IFNα, IFNβ and IFNλ, production or action are exquisitely susceptible to viral diseases such as herpes simplex encephalitis.
Presently, interferons are classified into three major groups distinguished by their structure, receptor usage and downstream effects. Type I (α, β and ω) IFNs are produced by leukocytes (α) and most cells (β) as a direct response to viral infection. There are 14-20 IFNα genes in mammals, but only one IFNβ gene. Type I IFNs are comprised of at least 12 functional IFN-α’s, one IFN-β, and one IFN-co species in human. Despite the large number of type I IFNs, they share a common receptor known as the type I IFN receptor (IFNAR), and activate the same signal transduction pathways to induce transcription of IFN-stimulated genes. They are also distinguishable by their sites of production. Type I IFNs are induced and secreted within hours after viral infection and thus they are a principal component of the innate immune response to viral infection.
Type II (γ) IFN, on the other hand, is produced by activated T lymphocytes and natural killer (NK) cells after recognition of infected cells. Mice in which IFN receptor genes are disrupted are particularly susceptible to viral infections, demonstrating the importance of the IFN system in antiviral defense. Type II IFN was not part of the biological activity described by Isaacs and Lindenman, but was named interferon by virtue of its potent antiviral effects. Type II IFN differs from the type I IFNs in both amino acid sequence and structure and binds to a unique receptor to activate distinct signaling pathways.
Type III interferon including IFNλ1, λ2, and λ3 (or IL-28a, IL-28b, and IL-29), signals similarly to type I IFNs.
Type I IFNs possess numerous biological activities. Broadly, their activities can be classified into four categories, although in certain cases, the effects may be related. In addition to their potent antiviral activity, type I IFNs have been shown to inhibit cellular proliferation, regulate apoptosis, as well as modulate numerous aspects of the immune response.
Like type I IFNs, IFN-γ also exerts potent antiviral effects in vitro. In fact, IFN-γ and type I IFNs exert overlapping, but non-redundant sets of biological activities both in vitro and in vivo, including inhibition of viral replication, inhibition of cellular proliferation and regulation of apoptosis. However, unlike type I IFNs, IFN-γ has unique physiological functions that have profound consequences in the immune response. Overall principal roles of IFN-γ are in the acquired immune response to intracellular pathogens and the development of an effective cellular immunity. IFN-γ has been implicated as an important mediator of tumor surveillance.
The effects of mutations in the IFN-γ pathway contrast with those of the type I and type III interferon pathways. Mutations in the IFN-γ receptor lead to Mendelian susceptibility to mycobacterial disease (MSMD), which is a predisposition to severe disease when infected by mycobacterial species such as Bacille Calmette-Guerin that are weakly virulent in healthy people. Study of human disorders has shown that IFN-y is necessary for proper immunity to mycobacteria and salmonella, but that it is most likely redundant for protection against many viral diseases. It therefore appears that, at least in humans, the major antiviral cytokines are likely the type I interferons and possibly the type III interferons.
The signaling of IFNs is a complex process. Once IFN binds to the receptor subunits—IFNAR1 and IFNAR2 for type I IFN, IFNGR1 and IFNGR2 for type II IFN, and CRF2-12 and CRF2-4 (IFNλR1 and 2) for type III IFN, heterodimerization and subsequent phosphorylation of the receptors is induced. Receptor heterodimerization causes tyrosine phosphorylation and activation of proteins in the Janus kinase (JAK) family, including JAK-1 and Tyk-2 for types I and III interferon, and JAK-1 and JAK-2 for type II IFN signaling. Once activated, the JAKs activate signal transducers and activators of transcription (Stats) by tyrosine phosphorylation. Stat-1 and Stat-2 are activated by types I and III IFN and Stat-1 is activated by type II IFN. The Stats heterodimerize (types I and III IFN) and associate with interferon regulatory factor 9 (IRF-9, also called p48) or homodimerize (type II IFN), translocate into the nucleus, and bind specific DNA sequences to induce transcription of interferon stimulated genes (ISGs). The complex including Stat-1, Stat-2, and IRF-9 is called interferon-stimulated gene factor 3 (ISGF3). It binds interferon-stimulated response elements (ISREs) in the promoter sequences of ISGs. The activated Stat-1 homodimer induced by IFN-γ signaling binds gamma activated sequences (GASs).
The type I IFN receptor (IFNAR) includes at least two subunits, IFNAR1 and IFNAR2, both of which are required for optimal ligand binding and signal transduction. Although IFNAR serves as a common receptor for all type I IFNs, not all type I IFNs exhibit the same affinities for the receptor. This has led some to speculate that an additional unidentified receptor subunit may determine differential responses to the different type I IFN subspecies.
Microarray studies of IFN treated human and murine cells have identified more than 300 Interferon Stimulated Genes (ISGs) which fall into many functional categories including: signaling, host defense, immune modulation, and inflammatory responses. Known enhancer sites such as GAS and ISRE can be found in the promoters of these genes, sometimes together or alone in single or multiple copies. The best characterized group of ISGs includes known antiviral genes. Examples include: OAS and RNASEL which inhibit a broad range of RNA viruses, PlvR. which shuts down translation, MX1 which disrupts trafficking of viral polymerases, and ISG-15 which is an ubiquitin-like protein that can modify viral proteins. The specific functions of many of the other identified ISGs remain unknown.
Of particular interest among the cytokines produced in response to central nervous system (CNS) viral infection is interferon beta (IFN beta). This molecule is the predominant interferon in the central nervous system and one of the first effector molecules produced in response to viral infection. As a Type I interferon, IFN beta belongs to a family that in humans includes interferon omega and the multiple subtypes of interferon alpha. The Type I interferons and interferon gamma, of the Type II class, stimulate the transcription of ISGs, which are often involved in host defense against viral infection. Interferon beta induces various transcriptional programs, some with inflammatory and others with anti-inflammatory effects, but it is difficult to overstate the importance of IFN beta as the initiator of potent antiviral cascades in the CNS. Small increases in IFN beta level evoke striking fluctuations in the levels of downstream molecules, e.g. the ISG myxovirus resistance protein (MxA or MX1). ISGs, some of which are transcription factors, may in turn affect production of additional proteins. All told, the ISGs number in the hundreds; for some, their antiviral activity, if any, remains unknown.