IFIT1 suppresses the infection of RSV by modulating microRNA-mediated regulation of IL1-b levels 9275

Abstract Description Interferon induced protein with tetratricopeptide repeats 1 (IFIT1) is an interferon stimulated gene with antiviral properties mediated through the translational inhibition of viral mRNAs that lack a 2’-O methyl group on their 5’ cap. IFIT1 expression is induced by activation of pattern recognition receptors, e.g. Toll-like receptors. Previously, we showed that IFIT1 differentially modulates the expression of various immune-related genes. IFIT1 positively regulates the type I interferon gene program in response to LPS stimulation-an effect mediated through modulation of an HDAC2 transcriptional regulatory complex-while also negatively regulating pro-inflammatory cytokine expression. We now show that IFIT1 negatively regulates miR-22 expression, an miRNA that inhibits translation of IL-b. Depletion of IFIT1 led to the upregulation of miR-22 and a consequent downregulation of intracellular IL1-b protein levels, along with strongly reduced IL1-b secretion in response to inflammasome activation. In IFIT1 depleted THP1 macrophages, reduced IL-1 levels led to increased infection by the OC43 coronavirus. We also found that RSV induced IL1-b expression was significantly diminished in Ifit1 knockout immortalized mouse macrophages (iMMs), leading to a significant increase in RSV infection levels. Our studies demonstrate a novel function for IFIT1 in supporting IL-1 dependent host defense against viral infection, through a miR-22-regulated circuit controlling IL1-b protein levels. Funding Sources This work was supported by the Intramural Research Program of NIAID, NIH and the Office of the AIDS Research at NIH Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)