Interferon-Induced Protein 44 and Interferon-Induced Protein 44-Like Restrict Replication of Respiratory Syncytial Virus.
Cellular intrinsic immunity, mediated by the expression of an array of interferon-stimulated antiviral genes, is a vital part of host defense. We have previously used a bioinformatic screen to identify two interferon-stimulated genes (ISG) with poorly characterized function, interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), as potentially being important in respiratory syncytial virus (RSV) infection. Using overexpression systems, CRISPR-Cas9-mediated knockout, and a knockout mouse model, we investigated the antiviral capability of these genes in the control of RSV replication. Overexpression of IFI44 or IFI44L was sufficient to restrict RSV infection at an early time postinfection. Knocking out these genes in mammalian airway epithelial cells increased levels of infection. Both genes express antiproliferative factors that have no effect on RSV attachment but reduce RSV replication in a minigenome assay. The loss of Ifi44 was associated with a more severe infection phenotype in a mouse model of infection. These studies demonstrate a function for IFI44 and IFI44L in controlling RSV infection.IMPORTANCE RSV infects all children under 2 years of age, but only a subset of children get severe disease. We hypothesize that susceptibility to severe RSV necessitating hospitalization in children without predefined risk factors is, in part, mediated at the antiviral gene level. However, there is a large array of antiviral genes, particularly in the ISG family, the mechanism of which is poorly understood. Having previously identified IFI44 and IFI44L as possible genes of interest in a bioinformatic screen, we dissected the function of these two genes in the control of RSV. Through a range of overexpression and knockout studies, we show that the genes are antiviral and antiproliferative. This study is important because IFI44 and IFI44L are upregulated after a wide range of viral infections, and IFI44L can serve as a diagnostic biomarker of viral infection.
['Busse|D C|DC|0000-0003-3872-3557', 'Habgood-Coote|D|D|', 'Clare|S|S|', 'Brandt|C|C|', 'Bassano|I|I|0000-0002-6948-2568', 'Kaforou|M|M|0000-0001-9878-4007', 'Herberg|J|J|0000-0001-6941-6491', 'Levin|M|M|0000-0003-2767-6919', 'Eléouët|J-F|JF|0000-0002-7361-4885', 'Kellam|P|P|0000-0003-3166-4734', 'Tregoning|J S|JS|0000-0001-8093-8741']
D000072283:A549 Cells D000818:Animals D000941:Antigens D001681:Biological Assay D064113:CRISPR-Cas Systems D045744:Cell Line, Tumor D003598:Cytoskeletal Proteins D004195:Disease Models, Animal D004847:Epithelial Cells D000072669:Gene Editing D005786:Gene Expression Regulation D057809:HEK293 Cells D054884:Host-Pathogen Interactions D006801:Humans D007113:Immunity, Innate D007223:Infant D051379:Mice D018345:Mice, Knockout D018357:Respiratory Syncytial Virus Infections D018113:Respiratory Syncytial Virus, Human D015398:Signal Transduction D025521:Tumor Suppressor Proteins D014779:Virus Replication
intrinsic immunity IFI44 RSV innate immunity restriction factor