http://hdl.handle.net/2123/19816
Title: | Parsing the roles of innate and adaptive immunity in lethal, type I interferon-driven, immunopathological disease in LCMV-infected STAT KO mice |
Authors: | Jung, So Ri |
Keywords: | LCMV STAT1 interferon |
Issue Date: | 8-Oct-2018 |
Publisher: | University of Sydney Faculty of Science School of Life and Environmental Sciences |
Abstract: | Type I interferons (IFN-I) have paradoxical roles in immune responses. While being key mediators of host responses to infectious agents and immunomodulators of innate and adaptive immunity through activation of interferon-stimulated gene factor 3 (ISGF3), a complex of STAT1, STAT2 and IRF9, these cytokines have pathological roles in autoinflammatory disorders. In parallel to the canonical signaling pathway, many reports highlight the pathophysiological roles of non-ISGF3, alternative IFN-I signaling pathways. Previously, the Campbell lab showed that unlike WT mice, STAT1 knock-out (KO) mice develop STAT2 and IRF9-dependent, IFN I dependent, CD4+ T-cell-mediated, lethal wasting disease following infection with a largely non cytopathic virus, lymphocytic choriomeningitis virus (LCMV). However, the molecular and cellular mechanisms by which the lethal disease is mediated in LCMV-infected STAT1 KO mice remain to be fully investigated. Based on the work in this project, we proposed a model of biphasic disease mediated by STAT1-independent, alternative IFN I signaling in these mice. The early phase involved innate immunity-driven, strong but transient IFN I production and IFN I-dependent, exaggerated, inflammatory responses. The late phase involved adaptive immunity-mediated, amplified, inflammatory responses. We showed that the combinatorial effects of these two phases are necessary for the lethal wasting disease in LCMV-infected STAT1 KO mice, as the ablation of the former by blocking IFN I signaling (STAT1/IFNAR double KO mice) or the latter by removing mature adaptive immune cells (STAT1/RAG1 double KO mice) prevented the death of the mice. These findings provide insight into the complex molecular and cellular requirements that determine whether IFN I play beneficial or detrimental roles during viral infection. Specifically, these findings further elucidate the pathophysiological roles of ISGF3-independent, alternative IFN I signaling during viral infection. |
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URI: | http://hdl.handle.net/2123/19816 |
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) |
File | Description | Size | Format | |
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jung_sr_thesis.pdf | Thesis | 36.16 MB | Adobe PDF |
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