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Towards a Quantitative Understanding of NF-kappaB and Interferon Signaling During the Cellular Response to Pathogens /


Acting quickly and transiently, the innate immune system is the first line of defense against incoming pathogens. An effective innate immune response by macrophages and other immune cells is critical to produce type I interferon beta (IFN[beta], other cytokines, and chemokines necessary to eliminate pathogens. The innate immune response activates complex signaling pathways that result in the activation of the nuclear factor -[kappa]B (NF[kappa]B) and interferon response factor (IRF) families of transcription factors. These factors coordinately bind to the IFN[beta] promoter to initiate transcription. Following activation, IFN[beta] is secreted and binds to the type I interferon receptor (IFNAR) to activate the interferon stimulated gene factor -3 (ISGF3), which stimulates hundreds of interferon-stimulated genes (ISGs). The positive physiological responses of IFN[beta] signaling are anti-viral, immunomodulatory, and anti- tumorigenic but inappropriate IFN responses can lead to autoimmune disease. Therefore IFN activation and downstream signaling is tightly regulated in response to pathogens. This dissertation describes our studies to provide a quantitative and predictive understanding of ISGF3 activation as well as NF[kappa]B and IRF control of IFN[beta] production. Chapter 1 provides an overview of the signaling pathways involved in the IFN response including receptor recognition of pathogens, transcription of IFN[beta], and ISGF3 activation by IFN[beta]. Chapter 2 describes a mathematical model of ISGF3 activation that is able to recapitulate IFN[beta] dose responses in multiple cell types. Chapter 3 presents genome-wide studies of physical interactions and genetic requirement to determine the contribution of IRF3 and ISGF3 in the gene expression response to double-stranded RNA (dsRNA). Chapter 4 reports our studies of the role of NF[kappa]B in IFN[beta] expression following toll-like receptor (TLR) and RIG-I- like receptor (RLR) stimulation. Finally, chapter 5 summarizes our findings and provides insight for future work

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