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Interferon
The molecular structure of human interferon-alpha (PDB: 1RH2​)
Identifiers
SymbolInterferons
PfamPF00143
InterProIPR000471
SMARTSM00076
PROSITEPDOC00225
CATH1au0
SCOP21au1 / SCOPe / SUPFAM
CDDcd00095
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Interferon type II (γ)
The three-dimensional structure of human interferon gamma (PDB: 1HIG​)
Identifiers
SymbolIFN-gamma
PfamPF00714
InterProIPR002069
CATH1d9cA00
SCOP2d1d9ca_ / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Interferon type III (λ)
Identifiers
SymbolIL28A
PfamPF15177
InterProIPR029177
CATH3og6A00
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Interferons (IFNs, /ˌɪntərˈfɪərɒn/ IN-tər-FEER-on[1]) are a group of signaling proteins[2] made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

IFNs belong to the large class of proteins known as cytokines, molecules used for communication between cells to trigger the protective defenses of the immune system that help eradicate pathogens.[3] Interferons are named for their ability to "interfere" with viral replication[3] by protecting cells from virus infections. However, virus-encoded genetic elements have the ability to antagonize the IFN response, contributing to viral pathogenesis and viral diseases.[4] IFNs also have various other functions: they activate immune cells, such as natural killer cells and macrophages, and they increase host defenses by up-regulating antigen presentation by virtue of increasing the expression of major histocompatibility complex (MHC) antigens. Certain symptoms of infections, such as fever, muscle pain and "flu-like symptoms", are also caused by the production of IFNs and other cytokines.

More than twenty distinct IFN genes and proteins have been identified in animals, including humans. They are typically divided among three classes: Type I IFN, Type II IFN, and Type III IFN. IFNs belonging to all three classes are important for fighting viral infections and for the regulation of the immune system.

Types of interferon

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Based on the type of receptor through which they signal, human interferons have been classified into three major types.

  • Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α/β receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains.[5] The type I interferons present in humans are IFN-α, IFN-β, IFN-ε, IFN-κ and IFN-ω.[6] Interferon beta (IFN-β) can be produced by all nucleated cells when they recognize that a virus has invaded them. The most prolific producers of IFN-α and IFN-β are plasmacytoid dendritic cells circulating in the blood. Monocytes and macrophages can also produce large amounts of type I interferons when stimulated by viral molecular patterns. The production of type I IFN-α is inhibited by another cytokine known as Interleukin-10. Once released, type I interferons bind to the IFN-α/β receptor on target cells, which leads to expression of proteins that will prevent the virus from producing and replicating its RNA and DNA.[7] Overall, IFN-α can be used to treat hepatitis B and C infections, while IFN-β can be used to treat multiple sclerosis.[3]
  • Interferon type II (IFN-γ in humans): This is also known as immune interferon and is activated by Interleukin-12.[3] Type II interferons are also released by cytotoxic T cells and type-1 T helper cells. However, they block the proliferation of type-2 T helper cells. The previous results in an inhibition of Th2 immune response and a further induction of Th1 immune response.[8] IFN type II binds to IFNGR, which consists of IFNGR1 and IFNGR2 chains.[3]
  • Interferon type III: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Although discovered more recently than type I and type II IFNs,[9] recent information demonstrates the importance of Type III IFNs in some types of virus or fungal infections.[10][11][12]

In general, type I and II interferons are responsible for regulating and activating the immune response.[3] Expression of type I and III IFNs can be induced in virtually all cell types upon recognition of viral components, especially nucleic acids, by cytoplasmic and endosomal receptors, whereas type II interferon is induced by cytokines such as IL-12, and its expression is restricted to immune cells such as T cells and NK cells.[13]

Function

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All interferons share several common effects: they are antiviral agents and they modulate functions of the immune system. Administration of Type I IFN has been shown experimentally to inhibit tumor growth in animals, but the beneficial action in human tumors has not been widely documented. A virus-infected cell releases viral particles that can infect nearby cells. However, the infected cell can protect neighboring cells against a potential infection of the virus by releasing interferons. In response to interferon, cells produce large amounts of an enzyme known as protein kinase R (PKR). This enzyme phosphorylates a protein known as eIF-2 in response to new viral infections; the phosphorylated eIF-2 forms an inactive complex with another protein, called eIF2B, to reduce protein synthesis within the cell. Another cellular enzyme, RNAse L—also induced by interferon action—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes. Inhibited protein synthesis impairs both virus replication and infected host cells. In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)—that have roles in combating viruses and other actions produced by interferon.[14][15] They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis.[16][17] The effect of IFN on p53 is also linked to its protective role against certain cancers.[16]

Another function of interferons is to up-regulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. All interferons significantly enhance the presentation of MHC I dependent antigens. Interferon gamma (IFN-gamma) also significantly stimulates the MHC II-dependent presentation of antigens. Higher MHC I expression increases presentation of viral and abnormal peptides from cancer cells to cytotoxic T cells, while the immunoproteasome processes these peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected or malignant cells. Higher MHC II expression increases presentation of these peptides to helper T cells; these cells release cytokines (such as more interferons and interleukins, among others) that signal to and co-ordinate the activity of other immune cells.[18][19][20]

Interferons can also suppress angiogenesis by down regulation of angiogenic stimuli deriving from tumor cells. They also suppress the proliferation of endothelial cells. Such suppression causes a decrease in tumor angiogenesis, a decrease in its vascularization and subsequent growth inhibition. Interferons, such as interferon gamma, directly activate other immune cells, such as macrophages and natural killer cells.[18][19][20]

Induction of interferons

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Production of interferons occurs mainly in response to microbes, such as viruses and bacteria, and their products. Binding of molecules uniquely found in microbes—viral glycoproteins, viral RNA, bacterial endotoxin (lipopolysaccharide), bacterial flagella, CpG motifs—by pattern recognition receptors, such as membrane bound toll like receptors or the cytoplasmic receptors RIG-I or MDA5, can trigger release of IFNs. Toll Like Receptor 3 (TLR3) is important for inducing interferons in response to the presence of double-stranded RNA viruses; the ligand for this receptor is double-stranded RNA (dsRNA). After binding dsRNA, this receptor activates the transcription factors IRF3 and NF-κB, which are important for initiating synthesis of many inflammatory proteins. RNA interference technology tools such as siRNA or vector-based reagents can either silence or stimulate interferon pathways.[21] Release of IFN from cells (specifically IFN-γ in lymphoid cells) is also induced by mitogens. Other cytokines, such as interleukin 1, interleukin 2, interleukin-12, tumor necrosis factor and colony-stimulating factor, can also enhance interferon production.[22]

Downstream signaling

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By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes; STATs are a family of transcription factors that regulate the expression of certain immune system genes. Some STATs are activated by both type I and type II IFNs. However each IFN type can also activate unique STATs.[23]

STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical Janus kinase-STAT (JAK-STAT) signaling pathway.[23] In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, phosphorylate both STAT1 and STAT2. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called IRF9—and moves into the cell nucleus. Inside the nucleus, the ISGF3 complex binds to specific nucleotide sequences called IFN-stimulated response elements (ISREs) in the promoters of certain genes, known as IFN stimulated genes ISGs. Binding of ISGF3 and other transcriptional complexes activated by IFN signaling to these specific regulatory elements induces transcription of those genes.[23] A collection of known ISGs is available on Interferome, a curated online database of ISGs (www.interferome.org);[24] Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters.[23] Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can occur only in the presence of a GAS element.[23]

In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades. For instance, both type I and type II IFNs activate a member of the CRK family of adaptor proteins called CRKL, a nuclear adaptor for STAT5 that also regulates signaling through the C3G/Rap1 pathway.[23] Type I IFNs further activate p38 mitogen-activated protein kinase (MAP kinase) to induce gene transcription.[23] Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is also regulated by both type I and type II IFNs. PI3K activates P70-S6 Kinase 1, an enzyme that increases protein synthesis and cell proliferation; phosphorylates ribosomal protein s6, which is involved in protein synthesis; and phosphorylates a translational repressor protein called eukaryotic translation-initiation factor 4E-binding protein 1 (EIF4EBP1) in order to deactivate it.[23]

Interferons can disrupt signaling by other stimuli. For example, interferon alpha induces RIG-G, which disrupts the CSN5-containing COP9 signalosome (CSN), a highly conserved multiprotein complex implicated in protein deneddylation, deubiquitination, and phosphorylation.[25] RIG-G has shown the capacity to inhibit NF-κB and STAT3 signaling in lung cancer cells, which demonstrates the potential of type I IFNs.[26]

Viral resistance to interferons

[edit]

Many viruses have evolved mechanisms to resist interferon activity.[27] They circumvent the IFN response by blocking downstream signaling events that occur after the cytokine binds to its receptor, by preventing further IFN production, and by inhibiting the functions of proteins that are induced by IFN.[28] Viruses that inhibit IFN signaling include Japanese Encephalitis Virus (JEV), dengue type 2 virus (DEN-2), and viruses of the herpesvirus family, such as human cytomegalovirus (HCMV) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8).[28][29] Viral proteins proven to affect IFN signaling include EBV nuclear antigen 1 (EBNA1) and EBV nuclear antigen 2 (EBNA-2) from Epstein-Barr virus, the large T antigen of Polyomavirus, the E7 protein of Human papillomavirus (HPV), and the B18R protein of vaccinia virus.[29][30] Reducing IFN-α activity may prevent signaling via STAT1, STAT2, or IRF9 (as with JEV infection) or through the JAK-STAT pathway (as with DEN-2 infection).[28] Several poxviruses encode soluble IFN receptor homologs—like the B18R protein of the vaccinia virus—that bind to and prevent IFN interacting with its cellular receptor, impeding communication between this cytokine and its target cells.[30] Some viruses can encode proteins that bind to double-stranded RNA (dsRNA) to prevent the activity of RNA-dependent protein kinases; this is the mechanism reovirus adopts using its sigma 3 (σ3) protein, and vaccinia virus employs using the gene product of its E3L gene, p25.[31][32][33] The ability of interferon to induce protein production from interferon stimulated genes (ISGs) can also be affected. Production of protein kinase R, for example, can be disrupted in cells infected with JEV.[28] Some viruses escape the anti-viral activities of interferons by gene (and thus protein) mutation. The H5N1 influenza virus, also known as bird flu, has resistance to interferon and other anti-viral cytokines that is attributed to a single amino acid change in its Non-Structural Protein 1 (NS1), although the precise mechanism of how this confers immunity is unclear.[34] The relative resistance of hepatitis C virus genotype I to interferon-based therapy has been attributed in part to homology between viral envelope protein E2 and host protein kinase R, a mediator of interferon-induced suppression of viral protein translation,[35][36] although mechanisms of acquired and intrinsic resistance to interferon therapy in HCV are polyfactorial.[37][38]

Coronavirus response

[edit]

Coronaviruses evade innate immunity during the first ten days of viral infection.[39] In the early stages of infection, SARS-CoV-2 induces an even lower interferon type I (IFN-I) response than SARS-CoV, which itself is a weak IFN-I inducer in human cells.[39][40] SARS-CoV-2 limits the IFN-III response as well.[41] Reduced numbers of plasmacytoid dendritic cells with age is associated with increased COVID-19 severity, possibly because these cells are substantial interferon producers.[42]

Ten percent of patients with life-threatening COVID-19 have autoantibodies against type I interferon.[42]

Delayed IFN-I response contributes to the pathogenic inflammation (cytokine storm) seen in later stages of COVID-19 disease.[43] Application of IFN-I prior to (or in the very early stages of) viral infection can be protective,[39] which should be validated in randomized clinical trials.[43]

With pegylated IFN lambda, the relative risk for hospitalization with the Omicron strains is reduced by about 80 %.[44]

Interferon therapy

[edit]
Three vials filled with human leukocyte interferon

Diseases

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Interferon beta-1a and interferon beta-1b are used to treat and control multiple sclerosis, an autoimmune disorder. This treatment may help in reducing attacks in relapsing-remitting multiple sclerosis[45] and slowing disease progression and activity in secondary progressive multiple sclerosis.[46]

Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for some cancers.[47] This treatment can be used in hematological malignancy, such as in leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, and cutaneous T-cell lymphoma.[47] Patients with recurrent melanomas receive recombinant IFN-α2b.[48]

Both hepatitis B and hepatitis C can be treated with IFN-α, often in combination with other antiviral drugs.[49][50] Some of those treated with interferon have a sustained virological response and can eliminate hepatitis virus in the case of hepatitis C. The most common strain of hepatitis C virus (HCV) worldwide—genotype I—[51] can be treated with interferon-α, ribavirin and protease inhibitors such as telaprevir,[52] boceprevir[53][54] or the nucleotide analog polymerase inhibitor sofosbuvir.[55] Biopsies of patients given the treatment show reductions in liver damage and cirrhosis. Control of chronic hepatitis C by IFN is associated with reduced hepatocellular carcinoma.[56] A single nucleotide polymorphism (SNP) in the gene encoding the type III interferon IFN-λ3 was found to be protective against chronic infection following proven HCV infection[57] and predicted treatment response to interferon-based regimens. The frequency of the SNP differed significantly by race, partly explaining observed differences in response to interferon therapy between European-Americans and African-Americans.[58]

Unconfirmed results suggested that interferon eye drops may be an effective treatment for people who have herpes simplex virus epithelial keratitis, a type of eye infection.[59] There is no clear evidence to suggest that removing the infected tissue (debridement) followed by interferon drops is an effective treatment approach for these types of eye infections.[59] Unconfirmed results suggested that the combination of interferon and an antiviral agent may speed the healing process compared to antiviral therapy alone.[59]

When used in systemic therapy, IFNs are mostly administered by an intramuscular injection. The injection of IFNs in the muscle or under the skin is generally well tolerated. The most frequent adverse effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. Erythema, pain, and hardness at the site of injection are also frequently observed. IFN therapy causes immunosuppression, in particular through neutropenia and can result in some infections manifesting in unusual ways.[60]

Drug formulations

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Pharmaceutical forms of interferons
Generic name Brand name
Interferon alfa Multiferon
Interferon alpha 2a Roferon A
Interferon alpha 2b Intron A/Reliferon/Uniferon
Human leukocyte Interferon-alpha (HuIFN-alpha-Le) Multiferon
Interferon beta 1a, liquid form Rebif
Interferon beta 1a, lyophilized Avonex
Interferon beta 1a, biogeneric (Iran) Cinnovex
Interferon beta 1b Betaseron / Betaferon
Interferon gamma 1b Actimmune
PEGylated interferon alpha 2a Pegasys
PEGylated interferon alpha 2a (Egypt) Reiferon Retard
PEGylated interferon alpha 2b PegIntron
Ropeginterferon alfa-2b Besremi
PEGylated interferon alpha 2b plus ribavirin (Canada) Pegetron

Several different types of interferons are approved for use in humans. One was first approved for medical use in 1986.[61] For example, in January 2001, the Food and Drug Administration (FDA) approved the use of PEGylated interferon-alpha in the USA; in this formulation, PEGylated interferon-alpha-2b (Pegintron), polyethylene glycol is linked to the interferon molecule to make the interferon last longer in the body. Approval for PEGylated interferon-alpha-2a (Pegasys) followed in October 2002. These PEGylated drugs are injected once weekly, rather than administering two or three times per week, as is necessary for conventional interferon-alpha. When used with the antiviral drug ribavirin, PEGylated interferon is effective in treatment of hepatitis C; at least 75% of people with hepatitis C genotypes 2 or 3 benefit from interferon treatment, although this is effective in less than 50% of people infected with genotype 1 (the more common form of hepatitis C virus in both the U.S. and Western Europe).[62][63][64] Interferon-containing regimens may also include protease inhibitors such as boceprevir and telaprevir.

There are also interferon-inducing drugs, notably tilorone[65] that is shown to be effective against Ebola virus.[66]

History

[edit]
Sidney Pestka of Rutgers University, seen here receiving the National Medal of Technology.

Interferons were first described in 1957 by Alick Isaacs and Jean Lindenmann at the National Institute for Medical Research in London;[67][68][69] the discovery was a result of their studies of viral interference. Viral interference refers to the inhibition of virus growth caused by previous exposure of cells to an active or a heat-inactivated virus. Isaacs and Lindenmann were working with a system that involved the inhibition of the growth of live influenza virus in chicken embryo chorioallantoic membranes by heat-inactivated influenza virus. Their experiments revealed that this interference was mediated by a protein released by cells in the heat-inactivated influenza virus-treated membranes. They published their results in 1957 naming the antiviral factor they had discovered interferon.[68] The findings of Isaacs and Lindenmann have been widely confirmed and corroborated in the literature.[70]

Furthermore, others may have made observations on interferons before the 1957 publication of Isaacs and Lindenmann. For example, during research to produce a more efficient vaccine for smallpox, Yasu-ichi Nagano and Yasuhiko Kojima—two Japanese virologists working at the Institute for Infectious Diseases at the University of Tokyo—noticed inhibition of viral growth in an area of rabbit-skin or testis previously inoculated with UV-inactivated virus. They hypothesised that some "viral inhibitory factor" was present in the tissues infected with virus and attempted to isolate and characterize this factor from tissue homogenates.[71] Independently, Monto Ho, in John Enders's lab, observed in 1957 that attenuated poliovirus conferred a species specific anti-viral effect in human amniotic cell cultures. They described these observations in a 1959 publication, naming the responsible factor viral inhibitory factor (VIF).[72] It took another fifteen to twenty years, using somatic cell genetics, to show that the interferon action gene and interferon gene reside in different human chromosomes.[73][74][75] The purification of human beta interferon did not occur until 1977. Y.H. Tan and his co-workers purified and produced biologically active, radio-labeled human beta interferon by superinducing the interferon gene in fibroblast cells, and they showed its active site contains tyrosine residues.[76][77] Tan's laboratory isolated sufficient amounts of human beta interferon to perform the first amino acid, sugar composition and N-terminal analyses.[78] They showed that human beta interferon was an unusually hydrophobic glycoprotein. This explained the large loss of interferon activity when preparations were transferred from test tube to test tube or from vessel to vessel during purification. The analyses showed the reality of interferon activity by chemical verification.[78][79][80][81] The purification of human alpha interferon was not reported until 1978. A series of publications from the laboratories of Sidney Pestka and Alan Waldman between 1978 and 1981, describe the purification of the type I interferons IFN-α and IFN-β.[69] By the early 1980s, genes for these interferons had been cloned, adding further definitive proof that interferons were responsible for interfering with viral replication.[82][83] Gene cloning also confirmed that IFN-α was encoded by a family of many related genes.[84] The type II IFN (IFN-γ) gene was also isolated around this time.[85]

Interferon was first synthesized manually at Rockefeller University in the lab of Dr. Bruce Merrifield, using solid phase peptide synthesis, one amino acid at a time. He later won the Nobel Prize in chemistry. Interferon was scarce and expensive until 1980, when the interferon gene was inserted into bacteria using recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures[86] or derived from yeasts. Interferon can also be produced by recombinant mammalian cells.[87] Before the early 1970s, large scale production of human interferon had been pioneered by Kari Cantell. He produced large amounts of human alpha interferon from large quantities of human white blood cells collected by the Finnish Blood Bank.[88] Large amounts of human beta interferon were made by superinducing the beta interferon gene in human fibroblast cells.[89][90]

Cantell's and Tan's methods of making large amounts of natural interferon were critical for chemical characterisation, clinical trials and the preparation of small amounts of interferon messenger RNA to clone the human alpha and beta interferon genes. The superinduced human beta interferon messenger RNA was prepared by Tan's lab for Cetus. to clone the human beta interferon gene in bacteria and the recombinant interferon was developed as 'betaseron' and approved for the treatment of MS. Superinduction of the human beta interferon gene was also used by Israeli scientists to manufacture human beta interferon.

Human interferons

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[6][91]

Teleost fish interferons

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[92][93]

References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Interferon

View on Grokipedia
from Grokipedia
Interferons are a family of cytokines produced by host cells in response to viral infections and other pathogens, acting as key mediators of the innate immune response by inducing an antiviral state in neighboring cells and coordinating broader immune defenses. Discovered in 1957 by Alick Isaacs and Jean Lindenmann during experiments on viral interference in influenza-infected chick embryo cells, interferons were initially characterized as soluble proteins that confer resistance to viral replication without directly neutralizing the virus. Interferons are categorized into three types based on their structure, receptor usage, and cellular sources: type I interferons (including over a dozen IFN-α subtypes, IFN-β, IFN-ε, IFN-κ, and IFN-ω), which are produced by most nucleated cells and bind the ubiquitously expressed IFNAR receptor; type II interferon (IFN-γ), secreted primarily by activated T cells and natural killer (NK) cells and binding the IFNGR receptor; and type III interferons (IFN-λ1 through IFN-λ4), mainly expressed by epithelial cells at mucosal surfaces and utilizing the IFNLR1/IL-10R2 receptor complex. These proteins exert pleiotropic effects, including direct antiviral activity through the upregulation of hundreds of interferon-stimulated genes (ISGs) such as MxA, OAS, and PKR that inhibit and spread; antiproliferative effects on tumor cells by arresting progression and promoting ; and immunomodulatory roles by enhancing NK cell , macrophage activation, via molecules, and differentiation of T cells and dendritic cells. Type I and III interferons share significant functional overlap in establishing early antiviral barriers, particularly at epithelial interfaces, while type II interferon uniquely drives Th1 immune responses and polarization critical for combating intracellular and tumors. Their signaling converges on the JAK-STAT pathway, leading to transcriptional activation of ISGs, but dysregulation can contribute to autoimmune diseases like systemic or exacerbate chronic inflammation. Clinically, recombinant interferons have been pivotal in treating conditions such as chronic hepatitis B and C infections, multiple sclerosis, and certain malignancies including hairy cell leukemia and melanoma, though their use has evolved with the advent of more targeted therapies due to side effects like flu-like symptoms and cytopenias. Ongoing research highlights their roles in emerging viral threats, cancer immunotherapy, and mucosal immunity, underscoring their enduring impact on biomedicine six decades after discovery.

Classification and Types

Type I Interferons

Type I interferons constitute a large family of cytokines that play a central role in the to viral infections. In humans, this family includes multiple subtypes of IFN-α, specifically 13 functional genes encoding the IFN-α subtypes (IFN-α1, IFN-α2, IFN-α4, IFN-α5, IFN-α6, IFN-α7, IFN-α8, IFN-α10, IFN-α13, IFN-α14, IFN-α16, IFN-α17, and IFN-α21), along with single genes for IFN-β, IFN-ε, IFN-κ, and IFN-ω, totaling 17 distinct subtypes. These proteins share a conserved structure consisting of five α-helices (A–E) arranged in a characteristic long-chain α-helical bundle, which facilitates their binding to cellular receptors and enables diverse biological activities. The of type I interferon is compact and clustered on the short arm of , spanning approximately 400 kb, with most lacking introns and consisting of a single . This arrangement, including 17 functional and several pseudogenes, reflects evolutionary duplication events that expanded the family. Notably, the IFN-κ gene is an exception, located separately on but still part of the broader cluster. Among these, IFN-α genes exhibit the greatest multiplicity, while IFN-β is encoded by a single inducible and exists as a monomeric protein. Key properties of type I interferons include their production by virtually all nucleated cells in response to viral pathogens, leading to rapid induction—often within hours of —via pattern recognition receptors. They bind exclusively to the heterodimeric IFNAR receptor complex (IFNAR1 and IFNAR2) on the cell surface, triggering shared signaling pathways that amplify antiviral states. These interferons primarily establish an antiviral milieu by inducing hundreds of interferon-stimulated genes, though their pleiotropic effects extend to immune modulation.

Type II Interferon

Type II interferon refers to a single , (IFN-γ), which is a dimeric protein lacking structural similarity to the alpha-helical bundles found in type I and type III interferons. Unlike the monomeric forms of other interferon types, IFN-γ forms a homodimer through non-covalent bonds in a unique head-to-tail orientation, featuring an intercalated arrangement of its six alpha helices per subunit. This compact structure, with a molecular weight of approximately 34-40 kDa for the dimer, enables high receptor specificity and distinct signaling capabilities. In humans, IFN-γ is encoded by the IFNG gene located on the long arm of at position 12q15. The gene spans about 5 kb and consists of four exons separated by three introns, with the mature protein derived from a 166-amino-acid precursor after cleavage of a 20-residue . This supports the production of a secreted that is heavily glycosylated at specific residues, contributing to its stability and bioactivity. IFN-γ is primarily secreted by activated natural killer (NK) cells and T lymphocytes, particularly CD4+ Th1 cells and CD8+ cytotoxic T cells, in response to immune challenges. It binds to a heterodimeric receptor complex composed of IFNGR1 and IFNGR2 subunits, initiating signaling that prominently activates macrophages to enhance antimicrobial activity and antigen presentation. This cytokine plays a pivotal role in promoting Th1-biased immune responses, driving cell-mediated immunity through upregulation of major histocompatibility complex class I and II molecules on target cells.

Type III Interferons

Type III interferons, also known as lambda interferons (IFN-λ), constitute a distinct subclass of interferons that exhibit structural homology to the interleukin-10 (IL-10) family of cytokines, with approximately 11–13% amino acid sequence identity to IL-10 and its relatives. These cytokines were identified as antiviral agents in the early 2000s and are characterized by their role in mucosal immunity, bridging innate antiviral responses with barrier-specific defense mechanisms. In humans, the type III interferon family comprises four members: IFN-λ1 (also designated IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B), and IFN-λ4. These proteins share 15–19% sequence homology with type I interferons, despite their classification in a separate family due to distinct receptor usage and expression patterns. The genes encoding IFN-λ1 through IFN-λ3 are tightly clustered on the long arm of human (19q13.13), spanning a region of about 40 kb, while the IFN-λ4 gene lies upstream of the IFNL3 gene; each gene is organized into five exons, reflecting a conserved genomic architecture typical of the IL-10 family. This clustering facilitates coordinated regulation during viral infections. A hallmark of type III interferons is their preferential production by epithelial cells lining mucosal barriers, such as those in the respiratory, gastrointestinal, and reproductive tracts, in response to viral pathogens like viruses. They exert their effects by binding to a unique heterodimeric receptor complex consisting of the IFN-λ-specific receptor subunit IFNLR1 (also known as IL-28Rα) and the shared IL-10 receptor β chain (IL10RB), which is distinct from the type I IFN receptor but activates similar Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. This receptor binding induces an antiviral state in target cells, comparable to that of type I interferons, by upregulating interferon-stimulated genes that inhibit , though the effects are more localized due to restricted IFNLR1 expression primarily on epithelial and select immune cells like dendritic cells and neutrophils. The epithelial-biased expression and limited receptor distribution of type III interferons minimize , providing targeted protection at entry points of infection without the widespread immune activation associated with type I interferons. Notably, genetic variations in the type III interferon locus influence disease outcomes; for instance, a dinucleotide frameshift variant (ss469415590) in the IFN-λ4 gene creates a functional protein but is associated with impaired spontaneous clearance of (HCV) infection, as individuals carrying the deleterious exhibit higher viral persistence rates in genome-wide association studies. This polymorphism highlights the clinical relevance of type III interferons in , where IFN-λ4 expression can modulate the balance between antiviral efficacy and immune pathology. Overall, the barrier-specific properties of type III interferons position them as key sentinels for mucosal antiviral defense, complementing the broader actions of other interferon classes.

Production and Induction

Cellular Sources

Interferons are produced by a variety of cells across different tissues, with production often being inducible in response to stimuli, though many cell types also exhibit basal low-level expression to maintain homeostatic antiviral readiness. This context-dependent expression allows interferons to contribute to both innate and adaptive immune responses, with specific cell types serving as primary producers for each interferon class. For type I interferons, plasmacytoid dendritic cells (pDCs) represent the major source of IFN-α, capable of producing vast quantities upon viral encounter due to their specialized expression. In contrast, IFN-β is predominantly secreted by fibroblasts, epithelial cells, and macrophages, which respond to a broader array of pathogens and provide localized antiviral protection. These cells, including endothelial cells, demonstrate widespread potential for type I interferon production, underscoring the ubiquity of this response in non-immune tissues. Type II interferon, IFN-γ, is primarily produced by adaptive immune cells such as + T helper type 1 (Th1) cells, + cytotoxic T cells, and natural killer (NK) cells, which release it during adaptive and innate immune activation. Additionally, monocytes and macrophages can generate IFN-γ upon appropriate stimulation, contributing to inflammatory contexts where myeloid cells amplify immune signaling. innate lymphoid cells (ILC1s) also serve as innate sources, linking early defense to subsequent T cell responses. Type III interferons, including IFN-λ, are chiefly produced by epithelial cells, particularly those lining mucosal barriers, where they enforce compartmentalized defense against enteric and respiratory pathogens. In the liver, hepatocytes emerge as key producers of IFN-λ during infections, such as and C, supporting organ-specific antiviral activity. Myeloid cells, like dendritic cells and macrophages, can also contribute to IFN-λ production in response to viral stimuli, though epithelial sources predominate at barrier sites.

Induction Pathways

Interferons are primarily induced in response to pathogen-associated molecular patterns (PAMPs) detected by receptors (PRRs) in innate immune cells. Viral infections trigger type I interferon production through endosomal and cytosolic sensors. Toll-like receptor 3 (TLR3), located in endosomes, recognizes double-stranded RNA (dsRNA) from viruses, recruiting the adaptor protein TRIF to activate both and interferon regulatory factor 3 (), which translocate to the nucleus to drive interferon . Cytoplasmic viral RNAs are sensed by RIG-I-like receptors (RLRs), including retinoic acid-inducible gene I (RIG-I) for short dsRNA with 5'-triphosphate ends and melanoma differentiation-associated protein 5 () for longer dsRNAs; both interact with (MAVS) to phosphorylate and activate and IRF7 via kinases such as TBK1 and IKKε. For DNA viruses or releasing cytosolic DNA, cyclic GMP-AMP synthase (cGAS) detects it and synthesizes the second messenger cGAMP, which binds and activates (STING) on the , leading to TBK1-mediated of and subsequent type I interferon transcription. Bacterial and parasitic infections engage additional pathways beyond viral sensors. Cytosolic bacterial DNA, such as from or , activates the STING pathway similarly to viral DNA, promoting IRF3-dependent type I interferon induction to enhance responses. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), including NOD1 and , recognize bacterial peptidoglycans in the ; , for instance, cooperates with RLRs to amplify IFN-β production during bacterial invasion by potentiating MAVS signaling. Parasitic triggers, such as protozoan DNA, also engage STING to induce type I interferons, contributing to control of infections like those caused by . Type I interferons (IFN-α and IFN-β) are induced via promoters containing interferon-stimulated response elements (ISREs) and binding sites, where phosphorylated and IRF7 form homodimers or heterodimers with to initiate transcription; IRF7 is particularly critical for IFN-α subtypes in plasmacytoid dendritic cells. Type III interferons are induced through pathways similar to type I, via PRR recognition of viral PAMPs leading to /IRF7 activation and transcription from promoters with ISRE and sites, predominantly in epithelial cells. In contrast, type II interferon (IFN-γ) production is mainly driven by adaptive immune signals, with (TCR) engagement in CD4+ and + T cells, combined with interleukin-12 (IL-12) stimulation from antigen-presenting cells, activating STAT4 and T-bet to promote IFN-γ in Th1 cells and natural killer cells. Transcriptional regulation of interferon genes relies on the cooperative action of , which drives proinflammatory genes alongside interferons, and IRFs, which specifically target interferon promoters; for example, the IFN-β enhanceosome assembles /7, , and AP-1 on the promoter to ensure robust induction. mechanisms, such as suppressors of cytokine signaling (SOCS) proteins—particularly SOCS1 induced by interferons themselves—inhibit (JAK)-STAT signaling upstream, limiting excessive interferon production to prevent .

Signal Transduction

Receptors and Binding

Type I interferons bind to a cell-surface receptor composed of the IFNAR1 and IFNAR2 subunits, forming a heterodimeric complex that facilitates high-affinity ligand engagement. IFNAR2 primarily mediates the initial high-affinity interaction with type I IFNs, exhibiting nanomolar binding affinity (Kd ≈ 0.1–100 nM depending on the IFN subtype), while IFNAR1 contributes lower-affinity binding (Kd ≈ 1–5 μM for IFNα subtypes). The resulting ternary complex achieves an overall affinity in the picomolar range (Kd ≈ 10^{-10} M), enabling efficient signal initiation across diverse cell types. Type II interferon (IFNγ) engages a receptor system comprising IFNGR1 and IFNGR2 subunits, which exist as preformed homodimers on the cell surface. binding by the dimeric IFNγ induces clustering of two IFNGR1 chains followed by recruitment of two IFNGR2 chains, assembling a 2:2:2 hexameric complex essential for signaling. This ligand-induced oligomerization enhances binding stability, with the IFNGR1-IFNγ interaction characterized by high affinity (Kd ≈ 10^{-9} to 10^{-10} M). Type III interferons (IFNλs) signal through a heterodimeric receptor of IFNLR1 and IL10RB subunits, with expression predominantly restricted to epithelial cells and certain immune cells at barrier sites. IFNLR1 provides the ligand-specific (Kd ≈ 10^{-7} to 10^{-8} M for IFNλ subtypes), while IL10RB serves as a shared low-affinity subunit common to IL-10 family cytokines. This epithelial-restricted distribution limits type III IFN responsiveness compared to the ubiquitous type I receptor. Structural studies reveal conserved cytokine-receptor interfaces across interferon types, featuring helical bundles in the ligands that dock into fibronectin type III domains on receptor chains. For type I IFNs, key interactions involve helix A and F of the IFN with IFNAR2's D1 domain and IFNAR1's membrane-proximal regions, stabilized by hydrogen bonds and hydrophobic contacts at the binding interface. Similar architecture in type III complexes highlights IFNLR1's role in anchoring IFNλ via its N-terminal helices. Receptor ubiquitination, particularly of IFNAR1 via SCF^βTrCP E3 ligase, promotes lysosomal degradation and desensitization, preventing prolonged signaling after ligand binding. Binding kinetics for interferons involve rapid association rates, such as 10^6–10^7 M^{-1} s^{-1} for type I IFNs to IFNAR, followed by quick dissociation modulated by subtype-specific affinities. Upon engagement, receptor-ligand complexes undergo swift clathrin-mediated , internalizing the complex within minutes to regulate signal duration and localization. This endocytic trafficking is crucial for balancing acute responses and avoiding overstimulation.

Downstream Signaling Cascades

Upon binding to their respective receptors, type I and type III interferons activate the kinase-signal transducer and activator of transcription (JAK-STAT) pathway through associated JAK1 and TYK2 kinases. This leads to tyrosine of STAT1 and STAT2, which heterodimerize and associate with interferon regulatory factor 9 (IRF9) to form the ISGF3 complex. The ISGF3 complex translocates to the nucleus and binds to interferon-stimulated response elements (ISRE) in the promoters of target genes, inducing their transcription. In contrast, type II interferon (IFN-γ) engages JAK1 and JAK2 kinases, resulting in and homodimerization of , which then binds to gamma-activated sites (GAS) to drive gene expression. These distinct STAT complexes ensure type-specific transcriptional programs while sharing core pathway components. Beyond the canonical JAK-STAT axis, interferons activate parallel pathways that modulate cellular responses. The (PI3K)/AKT pathway is engaged to promote cell survival and enhance translation of interferon-stimulated genes (ISGs) via /p70 S6 kinase activation. Additionally, (MAPK) cascades, including p38 and ERK, are induced to regulate proliferation and contribute to antiproliferative effects. These non-canonical signals integrate with JAK-STAT outputs to fine-tune interferon responses without altering the primary transcriptional machinery. Interferon signaling culminates in the induction of approximately 300 ISGs, including exemplars like MxA (which inhibits viral nucleocapsid assembly), OAS (which activates RNase L for RNA degradation), and PKR (which phosphorylates eIF2α to halt protein synthesis). These genes are primarily regulated through ISRE elements bound by ISGF3 for type I/III responses or GAS for type II. Signal amplification occurs via autocrine and paracrine loops, where induced interferons upregulate IFNAR expression to sustain pathway activation and propagate signals to neighboring cells. This feedback enhances the robustness of the antiviral and immunomodulatory state.

Biological Functions

Antiviral Mechanisms

Interferons establish an antiviral state in infected and neighboring cells primarily through the induction of interferon-stimulated genes (ISGs), which encode effector proteins that target multiple stages of the cycle. This state inhibits viral propagation by directly interfering with viral processes such as entry, replication, and protein synthesis, without relying on adaptive immune responses. One key mechanism involves the inhibition of synthesis via the double-stranded RNA (dsRNA)-activated R (PKR). Upon viral , dsRNA produced during replication activates PKR, leading to its autophosphorylation and subsequent of the 2 alpha (eIF2α) at serine 51. This inhibits the eIF2B, preventing the recycling of and thereby blocking the initiation of cap-dependent , which selectively impairs production while allowing some host to continue. PKR's role was first elucidated in studies showing its interferon-inducible activation as a core component of the antiviral response. Another major pathway is the 2'-5'-oligoadenylate synthetase (OAS)-RNase L system, which targets viral RNA for degradation. Interferon-induced OAS enzymes detect viral dsRNA and synthesize 2'-5'-linked oligoadenylates (2-5A), which bind and activate the latent endoribonuclease RNase L. Activated RNase L then cleaves single-stranded viral and cellular RNAs at UU/UA dinucleotides, resulting in the degradation of viral genomes and the production of small RNA fragments that can further amplify interferon signaling. This pathway's antiviral efficacy was demonstrated in early biochemical assays identifying OAS activation as a direct interferon effector. Specific ISGs also provide targeted antiviral actions. Mx GTPases, dynamin-like proteins induced by type I interferons, trap viral nucleocapsids and prevent their trafficking or assembly; for instance, human MxA inhibits by binding and sequestering viral ribonucleoproteins in the , blocking nuclear import essential for replication. APOBEC3G, an interferon-upregulated cytidine deaminase, incorporates into retroviral particles and hypermutates the viral genome by deaminating cytosines to uracils in the single-stranded DNA intermediate during reverse transcription, introducing deleterious G-to-A mutations that inactivate the . Similarly, IFITM proteins, particularly IFITM3, restrict viral entry by altering endosomal membrane fluidity and levels, thereby inhibiting fusion between viral and host membranes for enveloped viruses like and dengue. The establishment of this antiviral state is most effective when interferons are administered prior to or shortly after viral exposure, as pre-treatment allows full ISG expression and confers robust protection against subsequent , whereas concurrent treatment during active replication is less efficient due to partial pathway engagement.

Immunomodulatory Roles

Interferons play pivotal roles in modulating both innate and adaptive immune responses by facilitating communication between immune cells and promoting their differentiation and . Type I interferons (IFN-α and IFN-β) and type II interferon (IFN-γ) enhance the maturation of dendritic cells (DCs), which are crucial antigen-presenting cells. Specifically, type I IFNs upregulate the expression of (MHC) class I and II molecules on DCs, alongside costimulatory molecules such as and , thereby improving to T cells without halting . This maturation process is essential for bridging innate and adaptive immunity, as demonstrated in studies showing that systemic type I IFN responses are required for DC maturation and subsequent CD4+ T cell immunity during infections. Similarly, IFN-γ contributes to DC by enhancing MHC expression and promoting a pro-inflammatory that supports effective immune priming. In T cell responses, interferons direct differentiation toward protective effector subsets. IFN-γ, the canonical type II interferon, is a key driver of Th1 cell differentiation from naive CD4+ T cells, promoting the production of pro-inflammatory cytokines like IL-2 and further IFN-γ to amplify cellular immunity against intracellular pathogens. Type I IFNs complement this by enhancing the expansion and function of cytotoxic + T cells, increasing their survival and effector capabilities through STAT1-dependent signaling that boosts perforin and granzyme expression. Additionally, type I IFNs suppress Th2 responses by reversing Th2 commitment in human CD4+ T cells and inhibiting IL-4-mediated differentiation, thereby preventing allergic or humoral-biased immunity in favor of cell-mediated responses. Natural killer (NK) cells are activated by IFN-γ, which enhances their and production in a feedback loop that sustains innate antiviral and antitumor defenses. IFN-γ promotes NK cell proliferation and IFN-γ secretion itself, creating an autocrine amplification that recruits and activates other immune effectors. For B cells, type I IFNs influence class-switch recombination, particularly toward IgG subclasses like IgG2a and IgG3, by directly stimulating and indirectly via DC-mediated help, thereby enhancing humoral responses against viruses. Type III interferons (IFN-λ) exhibit similar but more localized effects on maturation in mucosal tissues. Interferons engage in complex crosstalk with other to fine-tune immune networks. IFN-γ synergizes with IL-12, produced by DCs and macrophages, to robustly induce Th1 differentiation and NK cell IFN-γ production, amplifying protective responses against infections and tumors. Conversely, interferons antagonize IL-10, an ; for instance, IFN-γ suppresses IL-10 production in macrophages, preventing dampening of pro-inflammatory signals and sustaining effector functions. Type I IFNs similarly counteract IL-10 by inhibiting its suppressive effects on DC maturation, ensuring sustained immune activation. This balanced interplay underscores interferons' role in orchestrating adaptive immune polarization.

Antiproliferative Effects

Interferons of all types exert antiproliferative effects through shared and distinct mechanisms, primarily involving the to induce arrest, , and suppression of tumor growth. These effects are mediated by the transcriptional of interferon-stimulated genes (ISGs) that regulate and survival. Type I interferons (IFN-α and IFN-β), upon binding to the IFNAR receptor, activate JAK1 and TYK2, leading to phosphorylation of and STAT2, which form the ISGF3 complex and drive ISG expression. A central mechanism is the STAT1-dependent upregulation of the inhibitor p21 (CDKN1A), which induces G1/S phase arrest by inhibiting CDK2 and preventing retinoblastoma protein (Rb) phosphorylation, thereby halting progression in tumor and proliferating cells. Type I IFNs also promote through pathways involving PKR , which phosphorylates eIF2α to inhibit protein synthesis, and upregulation of pro-apoptotic factors like and Bax, contributing to their efficacy against malignancies such as and . Type II interferon (IFN-γ) signals via the IFNGR receptor, primarily activating JAK1 and JAK2 to phosphorylate homodimers that directly induce antiproliferative genes. IFN-γ similarly upregulates p21 and downregulates cyclins (e.g., ), enforcing G1 arrest, and enhances in synergy with TNF-α by amplifying Fas and pathways. These effects are prominent in immune and epithelial cells, supporting antitumor immunity and restricting pathogen-induced proliferation. Type III interferons (IFN-λ) exert antiproliferative effects primarily through activation of the JAK-STAT signaling pathway, leading to the transcriptional regulation of genes that control cell growth and survival. Upon binding to the IFN-λ receptor complex (IFNLR1/IL10RB), IFN-λ induces phosphorylation of STAT1 and STAT2, forming the ISGF3 complex that drives expression of interferon-stimulated genes (ISGs) involved in growth inhibition. This mechanism shares similarities with type I IFNs (IFN-α/β), though IFN-λ often exhibits more sustained STAT activation and differential potency in epithelial and tumor cells. A key antiproliferative pathway involves STAT1-mediated upregulation of the cyclin-dependent kinase inhibitor p21 (CDKN1A), which promotes G1 phase cell cycle arrest by inhibiting CDK2 activity and preventing retinoblastoma protein (Rb) phosphorylation. IFN-λ also downregulates cyclins, such as cyclin D1 and E, further stalling the cell cycle progression in responsive cells like esophageal carcinoma lines and melanoma models. These effects mirror the G1 arrest induced by IFN-α/β but are more pronounced in IFN-λ-treated keratinocytes, where prolonged signaling enhances growth suppression. In addition to cell cycle control, IFN-λ induces in tumor cells through upregulation of pro-apoptotic factors, including and FAS ligands, activating cascades such as caspase-3/7. This pathway contributes to direct , with increased Bax expression and p21 accumulation amplifying death signals in IFN-λ-sensitive malignancies. Unlike IFN-γ, which synergizes with TNF-α to potentiate FAS/-mediated , IFN-λ's effects are more autonomous but can enhance overall antitumor responses in epithelial contexts. IFN-λ plays a role in by reinforcing p21-mediated growth arrest, contributing to long-term suppression of proliferation in aging or stressed cells, though this is less dominant than its acute antiproliferative actions. In normal cell , these mechanisms maintain epithelial integrity by limiting unchecked division, particularly at barrier sites. In tumor suppression, IFN-λ inhibits by inducing like IP-10 (), which recruit effector T cells and block (VEGF)-driven vessel formation in models of and . This indirect antiproliferative effect complements direct ISG-mediated growth control, enhancing remodeling without broad immune activation.

Interactions with Pathogens

Host Resistance to Viruses

Interferons play a pivotal role in the systemic host response to viral infections, orchestrating both innate and adaptive immunity through distinct temporal phases. Type I interferons, including IFN-α and IFN-β, initiate an early innate wave that rapidly establishes an antiviral state in infected and neighboring cells, limiting viral replication and spread shortly after pathogen detection.00746-9) This phase is crucial for containing initial infection before adaptive responses mature. Subsequently, Type II interferon (IFN-γ), produced primarily by activated natural killer cells and T lymphocytes, sustains the response by enhancing adaptive immunity, promoting cytotoxic T cell differentiation and antibody production to facilitate viral clearance. Together, these interferon types integrate innate control with long-term adaptive defenses, preventing dissemination and supporting resolution of acute infections. Specific examples illustrate interferons' contributions to organ-specific viral resistance. In influenza A virus infections, IFN-λ restricts viral propagation in the upper airways by inducing localized antiviral effects in epithelial cells, thereby preventing progression to the lower and reducing transmission risk. Similarly, in (HBV) infection, a robust interferon response correlates with viral control, whereas weak or impaired interferon signaling—characterized by diminished induction of interferon-stimulated genes (ISGs)—is associated with progression to chronicity, allowing persistent in hepatocytes. Experimental models underscore interferons' essentiality in host survival against viruses. In interferon receptor knockout mice, infection with lymphocytic choriomeningitis virus (LCMV) leads to lethal immune-mediated due to unchecked viral dissemination and dysregulated inflammation, highlighting the protective balance interferons impose on both antiviral defense and immune . Age and also modulate interferon efficacy; females generally exhibit stronger Type I interferon responses, conferring greater resistance to viral infections compared to males, while aging diminishes this response in both sexes, increasing susceptibility. These differences arise from sex-specific immune regulation and age-related declines in interferon signaling efficiency. Long-term immunity benefits from interferon-induced epigenetic modifications that imprint a "memory" on immune cells. In chronic viral infections, Type I interferons drive epigenetic changes in ISGs within memory B cells, enabling faster and more robust reactivation upon re-exposure, thus contributing to sustained protection without ongoing inflammation.00137-7) This mechanism ensures durable antiviral readiness, bridging acute responses to lifelong immunity.

Viral Countermeasures

Viruses have evolved diverse strategies to counteract the interferon (IFN) response, primarily by targeting its induction and signaling pathways to facilitate replication and dissemination. One prominent mechanism is the inhibition of IFN induction, where viral proteins interfere with pattern recognition receptors (PRRs) or downstream transcription factors. For instance, the nonstructural protein 1 (NSP1) of SARS-CoV prevents IFN production by blocking the phosphorylation and activation of interferon regulatory factor 3 (IRF3), a key transcription factor in the RIG-I/MDA5 pathway.00027-6/fulltext) Similarly, the NS1 protein of influenza A virus sequesters double-stranded RNA (dsRNA), a viral replication byproduct that would otherwise activate RIG-I and PKR, thereby suppressing IFN-β transcription and downstream antiviral gene expression. Another critical evasion tactic involves blockade of IFN receptors and signaling cascades, preventing the transduction of antiviral signals into the host cell. Poxviruses such as employ soluble decoy receptors like B18R, which bind type I IFNs with high affinity in the , competing with cellular receptors and inhibiting JAK-STAT . In HIV-1, the trans-activator of transcription (Tat) protein disrupts IFN-γ signaling by suppressing , thereby impairing the expression of IFN-stimulated genes (ISGs) essential for restricting viral spread. Certain virus families exhibit specialized countermeasures that modulate the IFN environment more broadly. Herpesviruses, including Epstein-Barr virus and human cytomegalovirus, encode homologs of interleukin-10 (vIL-10), which suppress pro-inflammatory cytokine production and indirectly dampen IFN responses by promoting an milieu that favors viral persistence. Picornaviruses, such as , utilize their 2A protease to cleave (MAVS), disrupting the RIG-I signaling adaptor and abolishing type I IFN induction at the mitochondrial membrane. RNA viruses often generate abundant immunostimulatory nucleic acids during replication, necessitating robust antagonism to evade rapid PRR detection. This ongoing between viruses and host PRRs has driven the diversification of IFN evasion mechanisms, with viral proteins adapting to counter emerging host defenses while hosts evolve enhanced sensing capabilities.30295-0)

Response in Coronaviruses

In infections, the type I interferon (IFN) response is characteristically delayed, permitting extensive in the early phase and subsequently driving hyperinflammation through exaggerated proinflammatory production. This temporal dysregulation contrasts with more robust early IFN responses seen in milder cases or other respiratory viruses, where prompt activation limits viral spread and mitigates tissue damage. In parallel, type III IFN (IFN-λ) exerts a protective effect confined to the upper airways, inducing antiviral interferon-stimulated genes (ISGs) in epithelial cells to restrict viral dissemination without eliciting the associated with type I IFN. Elevated IFN-λ1 and IFN-λ3 levels in the nasopharynx correlate with asymptomatic or mild outcomes, underscoring their role in frontline mucosal defense. Variant-specific differences in IFN induction further illustrate the nuanced host response to coronaviruses. The variant elicits a stronger type I and III IFN response than Delta, resulting in elevated ISG expression and reduced viral antagonism of innate signaling in primary nasal epithelial cells. This heightened sensitivity contributes to 's lower pathogenicity in the lower compared to earlier strains like Delta. Genetic factors also modulate severity; inborn errors in the type I IFN pathway, including autosomal recessive or dominant deficiencies in TLR3-, IRF7-, or IRF9-mediated signaling, impair antiviral immunity and predispose individuals to life-threatening , even without prior severe infections. Such monogenic defects account for up to 5% of critical cases, emphasizing the pathway's essentiality. Clinical investigations into IFN therapeutics have yielded promising results for coronavirus management. Phase II trials conducted in 2023 evaluated inhaled IFN-β1a (SNG001) in adults with mild-to-moderate COVID-19, demonstrating safety and a non-statistically significant reduction in hospitalization risk, alongside trends toward accelerated viral clearance and symptom resolution. These findings build on earlier evidence of IFN-β's antiviral potency against SARS-CoV-2, supporting its targeted delivery to the airways for enhanced local efficacy without broad immunosuppressive effects. SARS-CoV-2 counters the IFN response through accessory proteins that disrupt signaling cascades. Notably, ORF6 binds to nucleoporins and karyopherin complexes to block STAT1 nuclear translocation, thereby inhibiting type I IFN gene expression and ISG induction. Similarly, ORF9b localizes to the nucleolus and endoplasmic reticulum, where it interferes with STAT1 phosphorylation and translocation, enhancing viral evasion in infected cells. These mechanisms enable persistent replication and are amplified in certain variants, linking them to observed delays in host immunity. Persistent IFN dysregulation may underlie pathogenesis. Patients with ongoing post-acute sequelae exhibit chronically low serum levels of IFN-β and IFN-α, correlating with prolonged pulmonary complications and immune exhaustion. This subdued response contrasts with acute infection dynamics and suggests a failure to fully resolve the antiviral state, potentially sustaining low-grade . Emerging variants continue to evolve in IFN sensitivity, with progressive resistance observed across lineages of concern. Successive variants, including sublineages of , display diminished responsiveness to exogenous type I IFN , attributed to enhanced expression of antagonists like ORF6 and ORF9b, which may facilitate immune escape and prolonged shedding. Despite this, some post- strains retain partial susceptibility, informing ongoing and therapeutic strategies up to 2025.

Therapeutic Applications

Clinical Uses in Diseases

Interferons have established roles in treating various viral infections, particularly through type I interferons. Pegylated interferon-alpha (IFN-α), often combined with , was a standard therapy for chronic (HCV) prior to the introduction of direct-acting antivirals (DAAs), which have largely replaced it since achieving sustained virologic response (SVR) rates exceeding 95% with improved tolerability; historically, it achieved SVR rates of approximately 45-50% in patients with genotype 1 HCV. For chronic (HBV) , pegylated IFN-α-2a induces hepatitis B e-antigen (HBeAg) seroconversion in up to 36% of HBeAg-positive patients six months post-treatment. Type I IFN-β is approved for relapsing-remitting (MS), where it reduces the annualized relapse rate by about 30% compared to in large randomized trials. In , IFN-α serves as an for high-risk cutaneous , particularly in stage III disease, where high-dose regimens improve relapse-free survival without consistent overall survival benefits. For , IFN-α treatment yields overall response rates exceeding 80%, though complete remissions are achieved in fewer than 20% of cases, with durable responses in many patients. Type II IFN-γ is indicated for chronic granulomatous disease (CGD), a , where reduces the frequency and severity of serious infections by enhancing function, as demonstrated in controlled trials showing significant prophylactic . Emerging investigational applications for interferons include type III IFN-λ in autoimmune and infectious conditions. Recent 2024 clinical data support IFN-λ's role in management, with trials demonstrating its antiviral activity against , including reduced viral loads and potential prophylactic benefits in high-risk populations when administered as pegylated formulations; as of 2025, pegylated IFN-λ remains investigational for . However, interferon therapies face limitations in treatment due to poor long-term tolerance, including adverse effects like flu-like symptoms, mood disorders, and potential immune exhaustion, leading to limited and near-abandonment as a primary antiviral strategy.

Formulations and Administration

Interferon therapies are primarily available as recombinant formulations, with key examples including IFN-α2a (Roferon-A) and IFN-α2b (Intron A), which are produced via bacterial expression systems for treating viral infections and malignancies. Pegylated versions, such as IFN-α2a (Pegasys) and IFN-α2b (PegIntron), incorporate to extend and enable less frequent dosing compared to non-pegylated forms. For , IFN-β formulations include IFN-β1a (Avonex, administered intramuscularly) and IFN-β1b (Betaseron, administered subcutaneously). Administration typically occurs via subcutaneous or intramuscular injection, with pegylated interferons given once weekly to maintain therapeutic levels. For , dosing schedules vary: Avonex at 30 mcg intramuscularly once weekly, often titrated from 7.5 mcg to mitigate initial symptoms; Rebif (another IFN-β1a) at 44 mcg subcutaneously weekly after gradual escalation. Inhalation via nebulization is used for respiratory viral infections, such as with IFN-β1a (SNG001) or IFN-α2b , delivering the agent directly to the lungs to enhance local antiviral effects while minimizing systemic exposure. Common side effects include flu-like symptoms (fever, chills, ) occurring shortly after injection, affecting up to 60% of patients initially, as well as depression and dysfunction, particularly with IFN-α therapies. Management involves dose —starting at 20-25% of the full dose and increasing over weeks—to reduce symptom severity, alongside symptomatic treatments like analgesics or antidepressants. By 2025, biosimilars for IFN-α2a and other interferons have entered markets, offering comparable efficacy at 20-30% lower costs through competitive pricing and streamlined approvals. Emerging delivery systems, such as poly(lactic-glycolic acid) or chitosan-based carriers, are in preclinical and early clinical trials to enable sustained release, targeted or , and reduced by limiting systemic distribution.

Historical Development

Discovery and Early Characterization

The discovery of interferon took place in 1957 at the in , where Alick and Jean Lindenmann investigated the phenomenon of viral interference using fragments of chick embryo chorioallantoic membrane. They observed that cells exposed to heat-inactivated influenza virus became resistant to infection by live virus, a protection mediated by a diffusible, soluble factor released from the initially infected cells. This factor induced an antiviral state in uninfected neighboring cells without directly neutralizing the virus, distinguishing it from antibodies or other known immune components. and Lindenmann named the substance "interferon" to reflect its role in interfering with . In the early , research expanded to mammalian systems, with initial animal models demonstrating interferon's protective effects ; for instance, administration of interferon preparations reduced mortality from encephalomyocarditis virus in mice and protected rabbits from vaccinia virus lesions. By 1965, E. Frederick Wheelock reported the production of an interferon-like antiviral protein in human leukocytes stimulated by the mitogen phytohemagglutinin, marking the first identification of what would later be classified as a distinct type. During this decade, interferons began to be classified based on their cellular sources and properties: leukocyte-derived interferon (later designated alpha) and fibroblast-derived interferon (later beta) were distinguished by differences in antigenicity and production stimuli, though formal typing awaited further characterization. Alick Isaacs died prematurely in 1967 at age 46. The brought significant challenges in purifying interferon due to its low yields from natural sources—typically only 10^6 to 10^8 units per liter of supernatant or from blood—necessitating processing of vast quantities of material for even small amounts of pure protein. Efforts to isolate homogeneous interferon involved complex multi-step procedures like and , but instability and heterogeneity often resulted in substantial losses of activity. Despite these hurdles, partial purifications enabled early insights into its nature and species specificity, with human leukocyte interferon first purified to homogeneity in 1978. These advances set the stage for molecular studies, culminating in the cloning of interferon genes in the early .

Recombinant Production and Advances

The advent of recombinant DNA technology in the late 1970s enabled the large-scale production of interferons, overcoming the limitations of extracting them from biological sources such as virus-infected cells. In 1980, scientists at Genentech successfully cloned and expressed the human leukocyte interferon alpha (IFN-α) gene in Escherichia coli, marking the first production of recombinant IFN-α in a bacterial system and yielding biologically active protein at levels sufficient for initial therapeutic evaluation. This breakthrough, published in Nature, demonstrated that prokaryotic hosts could synthesize functional human cytokines, paving the way for industrial-scale manufacturing. Similarly, in the early 1980s, recombinant IFN-β was developed using Chinese hamster ovary (CHO) cells to produce a glycosylated form more akin to the native protein, addressing the need for proper post-translational modifications absent in bacterial expression systems. These early recombinant efforts culminated in regulatory milestones, with the U.S. (FDA) approving IFN-α2a (Roferon-A) and IFN-α2b (Intron A) in 1986 for the treatment of , the first approvals for any recombinant interferon and highlighting their antiproliferative potential in . However, production challenges emerged, particularly with bacterial hosts like E. coli, where the lack of led to reduced stability, shorter serum , and increased due to the formation of neutralizing antibodies in patients. Scale-up to levels also posed difficulties, requiring optimized processes to achieve high yields while minimizing inclusion body formation and endotoxin contamination, often necessitating refolding steps that complicated purification. Advances in the 1990s focused on improving through chemical modification. , the covalent attachment of (PEG) chains to IFN-α, was developed to extend circulating from hours to days, reducing dosing from daily to weekly injections and mitigating . This innovation, first explored in preclinical models around 1990 and leading to FDA approvals for pegylated IFN-α2a (Pegasys) and IFN-α2b (Peg-Intron) in 2002 for hepatitis C, represented a key refinement in recombinant interferon formulations. The 2000s saw the expansion of the interferon family with the discovery and recombinant development of type III interferons, known as IFN-λ (or lambda interferons). Identified in 2003 through genomic screening, IFN-λ genes were cloned and expressed in mammalian systems like CHO cells, revealing their unique receptor specificity on epithelial cells and potential for targeted antiviral therapy with reduced systemic side effects compared to type I IFNs. Initial recombinant production emphasized glycosylation to ensure bioactivity, with early studies demonstrating efficacy against hepatitis C and influenza in preclinical models. Recent progress from 2023 to 2025 has incorporated approaches to achieve sustained interferon expression, minimizing repeated dosing and immunogenicity risks associated with exogenous proteins. Adenoviral vectors, such as (Adstiladrin), which delivers the IFN-α2b gene for intravesical expression in , entered expanded clinical trials evaluating long-term safety and efficacy, with FDA approval of additional facilities in 2025 supporting broader access. In 2025, Japan's (PMDA) accepted a (NDA) filing for for high-risk BCG-unresponsive non-muscle invasive . In October 2025, presented new real-world research on its clinical use, including three studies at a medical conference. Ongoing phase II/III trials for similar vectors in viral infections and cancers aim to optimize integration for durable, localized IFN production, building on vector engineering to enhance transduction efficiency and reduce off-target effects. These developments underscore a shift toward integrated strategies, combining recombinant expression with advanced delivery systems for more precise therapeutic modulation.

Interferons in Specific Organisms

Human Interferons

Human interferons are encoded by a multigene family clustered primarily on specific chromosomes. The type I interferon genes, including 13 IFN-α genes (12 of which are functional and encode distinct subtypes), one IFN-β gene (IFNB1), one IFN-ε gene (IFNE1), one IFN-κ gene (IFNK), and one IFN-ω gene (IFNW1), are located in a cluster spanning approximately 400 kb on chromosome 9p21.3. The type II interferon, IFN-γ (IFNG), is encoded by a single gene on chromosome 12q15. Type III interferons, comprising IFN-λ1 (IFNL1), IFN-λ2 (IFNL2), IFN-λ3 (IFNL3), and IFN-λ4 (IFNL4, which functions as a pseudogene in many individuals but produces a protein in others), are clustered on chromosome 19q13.2 within a 55 kb region. This genomic organization reflects evolutionary duplication events, with the type I cluster containing at least nine pseudogenes, including several IFN-α pseudogenes such as IFNA1P, IFNA11P, and IFNA12P, which contribute to the complexity of interferon regulation without producing functional proteins. Genetic variations in interferon genes influence antiviral responses and susceptibility. A prominent polymorphism, rs12979860 in the IFN-λ3 gene (IFNL3), significantly affects spontaneous clearance and treatment response in () , with the CC conferring a favorable outcome by enhancing interferon signaling . differences are evident in IFN-α expression signatures, where females exhibit stronger type I interferon responses upon stimulation, driven by higher TLR7 expression on plasmacytoid dendritic cells and X-chromosome-linked factors, contributing to observed biases in autoimmune conditions. Recent single-cell sequencing (scRNA-seq) analyses have mapped interferon expression across tissues, revealing cell-type-specific patterns that highlight their role in immune . For instance, IFN-α and IFN-β are predominantly expressed in immune cells like plasmacytoid dendritic cells and monocytes in lymphoid tissues, while IFN-ε shows constitutive expression in epithelial cells of reproductive tissues; these insights from multi-organ atlases underscore dynamic regulation during and . Non-coding RNAs further modulate interferon , with long non-coding RNAs such as LUCAT1 acting as regulators to dampen type I interferon responses and prevent excessive . Human interferon genes bear signatures of evolutionary , including archaic from Neanderthals at loci like OAS1-OAS3, which encode interferon-stimulated genes enhancing antiviral activity against RNA viruses. Genome-wide association studies (GWAS) updated in 2025 have linked interferon pathway variants to autoimmune diseases, such as systemic (SLE), where trans-effects on interferon signaling genes like USP18 account for up to 9% of genetic risk, emphasizing their dual role in immunity and pathology.

Teleost Fish Interferons

Teleost fish, comprising the majority of extant fish , possess a diverse interferon (IFN) system that is integral to their innate antiviral immunity, differing significantly from that in higher vertebrates due to evolutionary adaptations such as whole-genome duplications. Type I IFNs are the primary antiviral cytokines in s, classified into three main groups based on structural features and phylogenetic analysis: group I (subgroups α, δ, ε, η), group II (subgroups β, γ, ζ, θ), and a more recently identified group III. Group I IFNs, characterized by four conserved residues forming two bonds, are present across all examined, while group II IFNs, with two cysteines forming a single bond, are restricted to specific lineages such as cyprinids (e.g., , ), salmonids (e.g., , ), and some perciforms. This structural diversity enables fish type I IFNs to bind distinct receptor complexes, enhancing their responsiveness to a broad spectrum of aquatic viruses. Structurally, type I IFNs belong to the class II α-helical family, featuring a characteristic four-helix bundle, but they exhibit greater sequence variability and genomic multiplicity compared to mammalian counterparts. Phylogenetic studies indicate that type I IFNs form a distinct separate from avian and mammalian type I IFNs, reflecting an ancient before the teleost-specific genome duplication events that amplified IFN numbers—up to 17 in salmonids like . For instance, in (Danio rerio), multiple IFN genes (e.g., ifnphi1 to ifnphi4) encode proteins with varying abilities to induce antiviral states, underscoring the system's adaptability to diverse viral threats in aquatic environments. Type II IFNs, represented by IFN-γ, are single-chain molecules that promote Th1-like responses and activation, while type III IFNs (IFN-λ) provide mucosal immunity, though less characterized in ; a type IV IFN, identified in 2022, functions similarly to type I but signals through unique family B (CRFB) members. Receptors for IFNs are encoded by the , which expanded in to include at least 17 members, allowing for specialized signaling. Type I group I IFNs primarily bind CRFB1/5/99 complexes, activating the JAK-STAT pathway to induce interferon-stimulated genes (ISGs) like mx, vig1, and isg15, which establish an antiviral state. In contrast, group II IFNs interact with CRFB2/5/99 or CRFB6/17/99 pairs, eliciting potent antiviral activity against RNA viruses such as virus (VHSV) in . Experimental overexpression of these IFNs in cell lines, such as epithelioma papulosum cyprini (EPC) cells, demonstrates dose-dependent protection against fish rhabdoviruses, with group II IFNs often showing higher potency due to their streamlined structure. The functional role of IFNs extends beyond antiviral defense to , with type I IFNs upregulating expression and enhancing NK cell-like activity in species like ginbuna . Seminal studies, including the initial of fish IFN genes in the early , revealed that poly I:C induction triggers IFN production via RIG-I-like receptors (RLRs), mirroring mammalian pathways but with greater reliance on LGP2 in fish. , recombinant IFN treatments in salmonids have reduced mortality from infectious salmon virus by over 80%, highlighting therapeutic potential in . However, the extraordinary diversity of fish type I IFNs—likely an evolutionary counter to sophisticated viral evasion tactics in water—also poses challenges, as some es like infectious hematopoietic virus (IHNV) can suppress IFN signaling via non-structural proteins. Recent advances, such as analyses of type I IFNα from large yellow croaker (), confirm the conserved helical fold but reveal unique loop regions that modulate receptor affinity, providing insights into ligand specificity absent in mammals. These findings, building on earlier work like the 2005 phylogenetic , emphasize the IFN system's role as a model for understanding and antiviral strategies in poikilothermic vertebrates.

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