The interferon-induced protein 44-like gene (i.e., IFI44L gene, also known as the GS3686, TLDC5B, and C1orf29 gene https://www.wikidata.org/wiki/Q18035986) codes for the interferon-induced protein 44-like protein (i.e., IFI44L protein). This gene is located in band 1, region 1 (see band and gene nomenclature) on the short, i.e., "p", arm of chromosome 1 (location abbreviated as 1p31.1). A closely related gene, the interferon-induced protein 44 gene (i.e. the IFI44 gene), is a paralog of the IFI44L gene (i.e., the two genes are duplicates of an ancestorial gene). The IFI44L and IFI44 proteins are composed of 452 and 444 amino acids, respectively, share 45% amino acid identity along with 60% homology at the amino acid level, and have many similar or overlapping functions and activities. This article focuses on the function and clinical significance of the IFI44L gene and the IFI44L protein that it directs to be formed.
The IFI444L gene is an interferon-stimulated gene in which type I interferons stimulate it to transcribe, i.e., make, its messenger RNA (mRNA) which in turn directs formation of the IFI44L protein. Type I interferons are cytokines which immune cells secrete in response to the accumulation of cytoplasmic DNA that occurs in microbe-infected cells, cancer cells, and cells with other types of injuries or abnormalities. Humans have 13 different type I interferon-α proteins: type I interferon-α1, -α2, - α4, -α5, -α6, -α7, -α8, - α10, -α13, - α14, -α16, -α17, -α21, and 4 other type I interferon proteins, type I interferon-β, -ε, -κ, and -Ω. These interferons bind to and stimulate the interferon-alpha/beta receptors located in a wide range of cells which when so stimulated act to promote or inhibit the inflammatory reactions associated with a various diseases and disorders including certain infections, cancers, genetic disorders, and autoimmune diseases. Diseases and disorders promoted by the type I interferons are termed interferon type I interferonopathies. Among the many genes that they influence, type I interferons stimulate cells to transcribe the IFI44L gene (see interferon-alpha/beta signaling) thereby increasing production of the IFI44L protein. Alterations in the expression of the IFI44L gene may be helpful in diagnosing and estimating the severity of various diseases and disorders and in some cases suggest that it may be targeted (i.e., stimulated or inhibited from forming IFI44L protein) to alter their development and/or progression.
Diseases and disorders associated with IFI44L gene abnormalities Viral infections Respiratory syncytial virus infections A 2016 study reviewing former publications on type I interferon-stimulated genes in lung infections caused by the respiratory syncytial virus (i.e., RSV) reported that the IFI44L gene was overexpressed in: a) the whole blood, peripheral blood mononuclear cells (i.e., PBMCs), oral mucosa, nasal mucosa, respiratory epithelium, and nasopharyngeal aspirates (i.e., suctions) of patients hospitalized for RSV infections; b) the cord blood of RSV-infected newborn infants; c) several different cultured human immortalized cell lines after being infected with RSV; and d) the lung tissue and whole blood of mice after being infected with RSV. A subsequent study found that: a) RSV stimulated cultured A549 cells (i.e., immortalized cells derived from human adenocarcinoma lung cells) to increase their IFI44L mRNA levels; b) intranasal injection of RSV into BALB/c mice increased the levels of IFI44L mRNA in their PBMCs; c) intranasal injection of RSV into C57BL/6N mice (i.e., mice that lack the IFI44L gene) developed greater weight losses and higher levels of RSV mRNA in their lung tissue than C57BL/6 mice (i.e., mice that have the IFI44L gene); d) cultured A549 cells that had their IFI44R gene disabled using gene knockout methods proliferated more rapidly than A549 cells that did not have this disablement; e) forced overexpression of the IFI44L gene in cultured 549 cells decreased their rate of proliferation; f) cultured A549 cells made to overexpress IFI44L mRNA had a lower percentage of cells that could be infected with RSV and a lower number of RSV recovered from their cultures; g) cultures of A549 cells made to express low levels of IFI44L mRNA and infected with RSV developed 2-fold higher levels of RSV than cultures of RSV-infected cells that expressed normal levels of IFI44L mRNA; and h) following intranasal inoculation with RSV, C57BL/6N mice, which lack functional IFI44L and IIFI44 genes, developed a far more severe RSV infection that mice lacking only one of these genes. The study also reported that 12 infants with severe RSV infections who were admitted to a hospital had significantly lower levels of IFI44L and IFI44 mRNA in their PBMCs than 6 infants with mild RSV who were admitted to this hospital. The study concluded that: a) high expression of the IFI44L gene reduces the growth of RSV and RSV-infected cells in cultured human lung cells and in mice; b) the increased expression of the IFI44L gene in infants infected with RSV is associated with significantly less severe disease than infants who expressed lower levels of the IFI44L gene; c) further studies are needed to confirm that overexpression of the IFI44L gene is associated with less severe RSV infections in infants infected with RSV, to determine if the IFI44L gene is overexpressed in children and adults with less severe RSV, to determine if the levels of this gene's expression would be useful for predicting the severity of RSV infection, and to determine if methods that promote overexpression of the IFI44L gene would be useful in treating RSV infections.
Influenza A virus, coronavirus, lymphocytic choriomeningitis virus, and COVID19 infections In contrast to the findings in RSV infections, cultured A549 cells infected with the Influenza A virus or the lymphocytic choriomeningitis virus and cultured Huh7 human liver cancer cells infected with the human coronavirus 229E: a) had far higher IFI44L mRNA levels than mock-infected cells; b) had reduced numbers of these viruses in their respective cells when their IFI44L genes were knocked out (i.e., deleted or inactivated); and c) knocking out the IFI44L gene also suppressed the expression of two interferon-induced proteins, IFIT2 and IFN-λ1. (IFIT2 and IFN-λ1 inhibit the growth and replication of various viruses.) These results indicate that the IFI44L protein promotes the proliferation of these three viruses in their respective cultured cells and appears to do so by inhibiting them from making two inhibitors of viral growth/proliferation, i.e., the type I interferon-stimulated IFIT2 protein and type III interferon-simulated IFN-λ1 protein. A study of 32 patients who had SARS-CoV-2, (a form of coronavirus that causes COVID-19) for 5 to 17 weeks reported that 15 patients with symptomatic covid-19 disease had significantly higher peripheral blood cell levels of IFI44L mRNA than 17 patients who did not develop symptoms of this infection. The study suggested that high blood cell levels IFI44L mRNA (and therefore IFI44L protein) contributes to the development of symptoms in patients with COVID-19 infections. An epigenome-wide association study on the DNA methylation of genes in individuals with Covid-19 reported that CpG sites (i.e., cytosine-phosphate-guanine sites) in a promotor (identified as the cg03607951 site ) of the IFI44L gene in the blood cells of 109 patients with Covid-19 had significantly lower levels of cytosine methylation than 71 non-infected individuals. Low levels of cytosine methylation in a gene's CPG promotor are usually associated with increases in the expression of this promotor's gene. This study supported the conclusion that high levels of IFI44L promote the development of symptomatic Covid-19 in humans.
Hepatitis B virus Hepatitis B virus (i.e., HBV) causes a form of chronic hepatitis that may lead to cirrhosis, cancer, and failure of the liver. HBV is a DNA virus that infects hepatocytes (i.e., liver cells) as a virion particle with its genetic material in the form of relaxed, circular DNA (i.e., rcDNA). Once inside the hepatocyte, it replicates by converting its rcDNA to covalently closed circular DNA (i.e., cccDNA: see rcDNA and cccDNA). cccDNA forms the proteins that transcribe the HBV DNA into mRNA and translate this mRNA into proteins that make HBV virions which leave the cell to infect other hepatocytes. As of 2024, there were 7 drugs licensed to treat chronic HBV hepatitis B infection in the United States(see treatment of chronic HBV hepatitis). These drugs suppress the replication of HBV but do not remove all of the HBV cccDNA, i.e., these drugs as well as various experimental treatments do not completely eliminate or inactivate cccDNA and therefore do not cure HBV-induced hepatitis. A study quantified the replication of HBV virions made by cultured Hep G2 human hepatocellular carcinoma cells by: a) infecting cultured Hep G2 cells with a form of HBV that causes severe liver damage in humans; b) adding the extracellular media of these Hep G2 cultures to cultures of PXB cells (i.e., human hepatocytes isolated from humanized PBX-mice); c) treating the cultured PXB cells with IFN-α, IFN-γ, or interferon-free culture medium on days 4, 8, 13, 18, and 23; and d) measuring the effects of these treatments on various indicators of HBV production. The culture media from untreated Hep G2 cells caused the PXB cells to develop progressively increasing levels of HBV virions and the HBsAg surface antigen of these virions over this 23 day period while the PXB cells, which were examined at day 23, developed increased levels of cccDNA, HBsAg, and HBV virions. In contrast, PXB cells treated with IFN-α or IFN-γ had increased levels of IFI44L mRNA and decreased levels of cccDNA, HBsAg and HBV virions while their media had decreased levels of HBV virions and HBsAg surface antigen. PXB cells that had their IFI44L partially knocked down showed far less of these IFN-α- and IFN-γ-induced changes. Thus, activation of the IFI44L gene appeared to suppress the intracellular replication of HBV and support studies to determine if it can be used to cure HBV infections in animal models and humans.
Early childhood respiratory tract infections