Role of a newly identified Interferon-Stimulated Gene, IFIRM, on Influenza A virus gene expression and replication

Abstract

Interferon is a major player in human innate immune defense system. Incoming viral infections trigger type-I/III interferon (IFN) expression and secretion, and in turn activate transcription of Interferon-Stimulated Genes (ISGs) to elicit antiviral functions and alter cellular signaling pathways. Some ISGs have board specificity towards various viruses and therefore can effectively terminate virus infection by means such as blocking viral entry and inhibiting virus replication. The identification of novel ISGs and characterization of their functions are important for the better understanding to human innate immune response, as well as the development of new therapeutic strategy. Our transcriptomic analysis on the IFN-treated normal human bronchial epithelial cells and two normal human lung fibroblast cell-lines identified more than hundreds of ISGs, and in this study we have characterized the antiviral role of a novel ISG, namely IFIRM, against influenza A virus infection. We showed in human lung cell lines that the expression of IFIRM was induced in an IFN-dependent manner through STAT2 conserve binding sequence found in the IFIRM promoter region. We then established a Tet-On cell line system to stably express IFIRM and determined its function during Influenza A virus infection. We showed that upon IFIRM overexpression, influenza H1N1 virus gene expression and replication are both attenuated, at both early and late infection. Our result showed that IFIRM was induced during IFN stimulation, and displayed antiviral activity towards Influenza A H1N1 virus. Interestingly, we found that the expression level of H1N1 viral mRNA was depleted in the presence of IFIRM overexpression, suggesting that the mechanistic action of IFIRM may be related to mRNA stability or translation efficiency. Our findings serve to provide understandings to IFIRM as an ISG during Influenza A virus infection and give insights to uncover its molecular antiviral mechanism. This study was supported by Research Grant Council - General Research Fund (17124317).