Ifitm3 is a member of the interferon-inducible transmembrane (IFITM) protein family and is encoded by the IFITM3 gene. It is highly expressed in cells of the myeloid lineage including monocytes, macrophages, and dendritic cells. It has also been detected in other cell types such as epithelial cells, endothelial cells, and fibroblasts. Ifitm3 functions as an antiviral protein that inhibits the replication of a variety of viruses including influenza A virus (IAV), dengue virus (DENV), West Nile virus (WNV), and HIV-1. The mechanism by which Ifitm3 exerts its antiviral activity is not fully understood but is thought to involve the direct interaction with viral proteins or interference with membrane fusion events required for viral entry into host cells.
Ifitm3 was first identified as a gene that was upregulated in response to type I interferon (IFN) treatment. Type I IFNs are a class of cytokines that are produced in response to viral infections and act to stimulate the innate immune response. Subsequent studies showed that Ifitm3 was induced by other proinflammatory stimuli such as Toll-like receptor ligands, lipopolysaccharide (LPS), and cytokines such as tumor necrosis factor alpha (TNFα). In addition to its induction by IFNs, Ifitm3 expression is also regulated at the transcriptional level by several transcription factors including NFκB, AP-1, STAT1, and IRF1/2.
The role of Ifitm3 in innate immunity was first demonstrated in mouse models of IAV infection where it was shown that ifitm3 knockout mice were more susceptible to IAV than wild-type mice. This increased susceptibility was associated with reduced levels ofIfitm3 mRNA and protein in the lungs of ifitm3 knockout mice following IAV infection. Additionally, ififrm2/5 double knockout mice, which lack two other members of the IFITM protein family, were also more susceptible to IAV than wild-type mice indicating that these proteins have redundant roles in limiting IAV replication. Further studies using mouse models have shown that Ifimt3 plays an important role in resistance to DENV infection as well as WNV infection. In both cases, ifimt3 knockout animals were more susceptible to these viruses than wild-type controls suggesting that this protein has broad anti-viral activity against multiple pathogens