interferon interferon interferons (ifns, /ˌɪntərˈfɪərɒn/) are a group of signaling proteins 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. interferon type i (α/β/δ...)the molecular structure of human interferon-alpha (pdb: 1rh2​)identifierssymbolinterferonspfampf00143interproipr000471smartsm00076prositepdoc00225cath1au0scop21au1 / scope / supfamcddcd00095available protein structures:pfam structures / ecod pdbrcsb pdb; pdbe; pdbjpdbsumstructure summary interferon type ii (γ)the three-dimensional structure of human interferon gamma (pdb: 1hig​)identifierssymbolifn-gammapfampf00714interproipr002069cath1d9ca00scop2d1d9ca_ / scope / supfamavailable protein structures:pfam structures / ecod pdbrcsb pdb; pdbe; pdbjpdbsumstructure summary interferon type iii (λ)identifierssymbolil28apfampf15177interproipr029177cath3og6a00available protein structures:pfam structures / ecod pdbrcsb pdb; pdbe; pdbjpdbsumstructure summary 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. interferons are named for their ability to "interfere" with viral replication 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. 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 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. the type i interferons present in humans are ifn-α, ifn-β, ifn-ε, ifn-κ and ifn-ω. in general, type i interferons are produced when the body recognizes a virus that has invaded it. they are produced by fibroblasts and monocytes. however, the production of type i ifn-α is inhibited by another cytokine known as interleukin-10. once released, type i interferons bind to specific receptors on target cells, which leads to expression of proteins that will prevent the virus from producing and replicating its rna and dna. overall, ifn-α can be used to treat hepatitis b and c infections, while ifn-β can be used to treat multiple sclerosis. interferon type ii (ifn-γ in humans): this is also known as immune interferon and is activated by interleukin-12. 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. ifn type ii binds to ifngr, which consists of ifngr1 and ifngr2 chains. 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, recent information demonstrates the importance of type iii ifns in some types of virus or fungal infections. in general, type i and ii interferons are responsible for regulating and activating the immune response. 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. function 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. they also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis. the effect of ifn on p53 is also linked to its protective role against certain cancers. 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. 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. induction of interferons 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. 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. downstream signaling 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. stat activation initiates the most well-defined cell signaling pathway for all ifns, the classical janus kinase-stat (jak-stat) signaling pathway. 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. a collection of known isgs is available on interferome, a curated online database of isgs (www.interferome.org); 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. 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. 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. type i ifns further activate p38 mitogen-activated protein kinase (map kinase) to induce gene transcription. 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. 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. 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. viral resistance to interferons many viruses have evolved mechanisms to resist interferon activity. 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. 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). 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. 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). 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. 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. 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. 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. 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, although mechanisms of acquired and intrinsic resistance to interferon therapy in hcv are polyfactorial. coronavirus response coronaviruses evade innate immunity during the first ten days of viral infection. 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. sars-cov-2 limits the ifn-iii response as well. reduced numbers