Gale, Jr., MichaelAarreberg, Lauren Danielle2019-05-022019-05-022019Aarreberg_washington_0250E_19384.pdfhttp://hdl.handle.net/1773/43701Thesis (Ph.D.)--University of Washington, 2019Interleukin-1 beta (IL-1β) is a pleiotropic mediator of inflammation and is produced in response to a wide range of stimuli. During infection, IL-1β production occurs in parallel with the onset of innate antimicrobial defenses, but the contribution of IL-1β signaling to cell-intrinsic immunity is not defined. Induction of interferon (IFN), IFN-stimulated genes (ISG) and inflammatory responses are critical for control of viral infection. We recently identified an essential linkage between stimulation of the inflammatory cytokine IL-1β and induction of ISGs that function as host restriction pathways against the emerging flavivirus, West Nile virus (WNV), in vivo. We utilized ex vivo global transcriptome analysis of primary dendritic cells, known targets of WNV replication, to define gene signatures required for this IL-1β-driven antiviral response. Dendritic cells that were deficient in IL-1 receptor signaling showed dysregulation of cell-intrinsic defense genes and loss of viral control during WNV infection. We found that IL-1β treatment, in the absence of infection, drove transcription of IFN and ISGs at late times following treatment. In delineating the mechanism of IL-1β-to-IFN signaling crosstalk, we found that exogenous IL-1β induces interferon regulatory factor 3 (IRF3) activation in human myeloid, fibroblast and epithelial cells. IRF3 activation by IL-1β is dependent upon the DNA sensing pathway adaptor, stimulator of interferon genes (STING), through the recognition of cytosolic mitochondrial DNA by cyclic GMP-AMP synthase (cGAS). IL-1β treatment results in IFN production and activation of IFN signaling to direct a potent innate immune response that also restricts Dengue virus infection. This study identifies a new function for IL-1β in the onset or enhancement of cell-intrinsic immunity, with important implications for cGAS-STING in integrating inflammatory and microbial cues for host defense.application/pdfen-USCC BY-NC-NDAntiviralDengue virusInnate immune activationInterleukin-1STINGWest Nile virusImmunologyCellular biologyMolecular biologyImmunologyThesis