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Dissertation
Characterization of Cell Type-Specific Responses to Interferons in the Central Nervous System
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2013
DOI:
https://doi.org/10.17918/00000596
Abstract
The immune system can effectively combat viral infections within the central nervous system (CNS), although the mechanisms by which neurons respond to inflammatory mediators remain largely undefined. Interferon gamma (IFN-[gamma]) and interferon-beta (IFN-13) are potent anti-viral cytokines which classically signal through rapid and robust activation of STAT molecules that directly affect gene expression. However, activation of STAT1 is muted and delayed in primary hippocampal neurons treated with IFN-[gamma] when compared to mouse embryonic fibroblasts (MEF). We examined the kinetics of STAT1 and STAT2 activation in response to type I interferon. We have found that these kinetics differ in neurons and MEF, with significant differences in the resulting pattern of gene expression. Despite lower basal expression of select ISGs in neurons, basal expression of type I interferons themselves is significantly higher in neurons compared to MEF. This increased basal expression of interferons in neurons is critical and sufficient for early control of viral infection. We demonstrated a requirement for interferon signaling in early control of viral infection in vivo, while confirming that survival during viral infection in the absence of type I interferon is virus-specific. Next, we examined the effect of type I interferon priming on IFN-[gamma] signaling in neurons and MEF. We found that priming neurons with IFN-13 alters the cellular response to subsequent IFN-[gamma] exposure. While IFN-13 priming increases the kinetics with which STAT1 is activated following IFN-[gamma] exposure, downstream IFN-[gamma]-induced gene expression is dampened in neurons but not MEF. Interestingly, serial exposure to IFN-[beta] and IFN-[gamma] does not affect protection from infection with measles virus than exposure to either cytokine alone. Collectively, these data support the hypothesis that neurons utilize distinct signaling pathways in response to cytokines. Type I interferon signaling in neurons may play a protective role in priming cells of the CNS for the potentially cytotoxic effects of IFN-[gamma] and other cytokines. We propose that cell type-specific differences in type I interferon signaling play a role in the ability of neurons to survive viral infection.
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Details
- Title
- Characterization of Cell Type-Specific Responses to Interferons in the Central Nervous System
- Creators
- Sarah E. Cavanaugh
- Contributors
- Glenn Rall (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 175 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970228604721