|Title:||Investigation of Type I Interferon Signaling in the Cellular Response and Host Defense|
|Keywords:||central nervous system (CNS)|
interferon regulator factor 7 (IRF7)
lymphocytic choriomeningitis virus (LCMV)
signal transducers and activators of transcription (STAT)
type I interferons (IFN-I)
|Publisher:||University of Sydney.|
School of Molecular Bioscience.
|Abstract:||Type I interferons (IFN-I) mediate the antiviral host response through activation of interferon-stimulated gene factor 3 (ISGF3) complex consisting of STAT1, STAT2 and IRF9. However, IFN-I can activate a number of non-canonical signaling pathways, which may contribute to neurological diseases in transgenic mice with CNS-production of IFN-α. It remained largely unknown how and to what extent non-canonical signaling pathways mediate the functional effects of IFN-I. Thus, the role of IFN-α-stimulated ISGF3-independent gene regulation was investigated in murine primary mixed glial cells (MGCs) in the absence or presence of STAT1, STAT2 or IRF9 using global gene expression profiling. This study revealed for the first time the existence of non-ISGF3 dependent IFN-I signaling pathways, primarily dependent on STAT1 and STAT2. Several possible target genes (e.g. IRF7) were identified to be involved in mediating the adverse effects of IFN-I in the CNS. IRF7 is a key regulator of IFN-I production. STAT1 KO mice following lymphocytic choriomeningitis virus (LCMV) infection develop a unique lethal disease associated with excessive serum IFN-I production. The STAT1-independent induction of IRF7 following LCMV infection has been reported previously. Thus, we investigated whether IRF7-induced IFN-I production is involved in the lethal host response to LCMV in STAT1 KO mice. This study demonstrated that IRF7 is required for the early innate control of LCMV infection, likely through the regulation of the appropriate IFN-I response, and is not required for the antiviral CD8+ T-cell-dependent clearance of LCMV. Furthermore, these studies indicated that the lethal immune-mediated disease resulting from LCMV infection in STAT1 KO mice is dependent on IRF7-induced IFN-I production, and is driven by non-canonical IFN-I signaling via STAT2 and IRF9. These studies highlight how IFN-I mediates cellular response via non-canonical IFN-I signaling in CNS and in host defense against LCMV infection.|
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|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|li_wl_thesis.pdf||PhD Thesis||28.62 MB||Adobe PDF|
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