Interferon omega-1 is aprotein that is encoded by theIFNW1gene.[3][4]
Interferon omega-1 (IFN-ω) is a subtype of theInterferon type I family. The Interferon Type 1 family is made up ofcytokines (proteins used in cell signaling) which bind to the cell surface receptor IFNAR. They are found in mammals and play roles in immunoregulation, inflammation,T-cell response, and tumor cell identification. Type 1 Interferons have also been found in birds, lizards, and turtles. Multiple subvarients of IFN-ω have been observed in non-primate mammals with placentas.[5][6] IFN-ω has been linked to antitumor activity and protection against bacterial and parasitic pathogens.[7]
Throughgenome sequence analysis, it’s thought that the IFN-ω gene diverged from the IFN-α gene roughly 130 million years ago. Interferon omega-1 serves as cytokines which promote innate immunity against viruses and cancers. They are involved with almost every nucleated cell.[7]
There are sixteen sub-types of Interferon type I. Despite having roughly 20%-60% sequence identity, the subtypes each act onIFNAR1 orIFNAR2 subunits of the class two helical cytokine receptor family. Specifically, IFN-ω shares 33% sequence similarity with IFN-β and 62% sequence similarity with IFN-α.[7]The IFNAR1 subunit contains an intracellular domain which is linked toTyrosine kinase 2 and the IFNAR2 subunit contains an intracellular domain that is linked toJanus kinase 1. Once bound to these tyrosine kinases a [phosphorylation] cascade will progress and is regulated by theSTAT protein. Different responses result from the binding of each type I Interferon and evidence points to the cause being conformational differences in ligand-receptor binding. The receptor can bind each type I Interferon in unique ways, creating respective downstream effects for each variant.[8]
As of writing, limited IFN-ω structures are publicly available. There has been a structure of the IFNω-IFNAR ternary complex which has been solved to a resolution of 3.5angstroms viaX-ray crystallography.[8] From this structure, the protein consists of four long and aligned alpha helices and one short alpha helix connection. It is bound to both subunits simultaneously and with each active site being at opposite ends of the protein. In this structure there is a small molecule of NAG bound to IFNAR1 on the opposite side of IFN-ω binding.[8]
The Arg35 residue in IFN-ω is one which binds to the IFNAR2 subunit and is conserved across most IFN type I subvarients. Leu32 of IFN-ω is another conserved residue in thehydrophobic cluster involved in IFNAR2 binding. The Val80 residue of IFNAR2 has shown to be key in discriminating between Type 1 Interferon subtypes and has a large effect on IFN-ω binding.[8]
For binding with the IFNAR1 subunit, the residue Phe67 of IFN-ω has key hydrophobic and aromatic interactions with the Leu134 residue of IFNAR1. Additional hotspot residues include Arg123 of IFN-ω and Tyr70 or the IFNAR1 subunit. Asalt bridge is formed between Lys152 and Glu149 of IFN-ω and in a small distance from Glu77 of IFNAR1. When bound to IFN-ω, the SD1 of IFNAR1 undergoes a major conformational change that is not seen when unbound or bound to IFN-α2.[8]
A study reported correlation between a decreased level of Interferon type I proteins and more severeCOVID-19 cases that are not associated with detectable autoantibodies against IFN-ω or IFN-α.[9]
IFN-ω has been licensed in several countries to treatcanine parvovirus,feline leukemia virus, andfeline immunodeficiency virus infections. However, due to expense and a time-consuming protocol of 15 total rounds ofsubcutaneous administration, its use remains limited. In guinea pigs, it has been found to significantly reduce viral loads ofInfluenza A virus subtype H1N1 upon daily treatment. A limiting factor in its therapeutic use is the recombinant protein’s short half-life, and this can potentially be worked around with techniques such asPEGylation.[7]
Although it hasn’t been licensed for therapeutic use, IFN-ω has been found to decrease the viral load ofEnterovirus E, infectious bovine rhinotracheitis virus,Bovine viral diarrhea,Indiana vesiculovirus,pseudorabies virus, European bat lyssavirus,influenza virus,feline calicivirus, and feline herpesvirus-1 (FHV-1). However, further studies are needed to reinforce these claims.[7]
In combination withribavirin, IFN-α has been used to treat chronichepatitis C virus infections, however, this treatment option can carry extreme side effects. Evidence has emerged that IFN-ω could also serve as a potential treatment for HCV as it is more potent than IFN-α in repressing HCV RNA replicons.[7]
Although limitations include time-consumption, necessary facilities, lack of specificity, and use of radioisotopes, IFN-ω can be used in the detection of APS-1. Anti-IFN-ω antibodies are shown to develop before APS-1 symptoms show which allow for early detection of the virus. Methods of antibody detection includeimmunoassay,radioligand binding assay, and antiviral neutralization assays.[7]
Studies have also shown IFN-ω to treat numerous diseases in felines and canines, however, further studies are needed with larger sample sizes and controlled groups to ensure accuracy of results. There is also evidence of antitumor effects on human tumor xenografts in nude mice.[10]
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