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Dissertation
Interferons Induce BST-2/tetherin in Measles Virus-Infected Neurons and Permissive Mice
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2013
DOI:
https://doi.org/10.17918/00000982
Abstract
Though neurons can be productively infected with measles virus (MV), they do not display two of the cardinal hallmarks of peripheral infection: release of extracellular virions and associated cytopathicity due to syncytia formation. How neurons survive MV infection, as well as other neurotropic viral infections, may be due to induction of a unique profile of interferon-inducible genes. One of these genes, BST-2, inhibits release of enveloped viruses. Based on this observation, we investigated the ability of interferons and MV infection to induce BST-2 in primary neurons, and to explore the consequences of BST-2 expression on MV release. Despite low basal BST-2 expression in neurons as compared to primary fibroblasts and glial cells, Type I (IFN[beta]) and Type II interferon (IFN[gamma]) exposure significantly induced BST-2 expression in neurons. MV-infection of neurons also elevated BST-2 levels, though interestingly, another enveloped RNA virus, lymphocytic choriomeningitis virus (LCMV), did not affect BST-2 levels, perhaps because of its capacity to block the host interferon response. This finding led us to investigate how MV induces BST-2. Utilizing neurons from Type I interferon receptor knockout (IFNAR KO) mice and STAT1 knockout mice, we found that MV upregulation of BST-2 is dependent on IFN production and signaling via STAT1, not viral replication itself. A cell line expressing tetracycline-inducible BST-2 was employed to show that extracellular MV is, in fact, limited by BST-2 expression. Historically, interferons are known to inhibit viral spread and contain infection. Moreover, IFN[gamma] is recognized as a critical mediator of neurotropic MV infection. Although IFN[gamma] is crucial for non-cytolytic clearance of MV in vivo, the mechanisms by which it protects neurons from death and viral release are unknown. Type I interferons and IFNy were examined for their ability to limit viral RNA production and spread. Of note, Type I interferons and IFN[gamma] inhibited MV via different mechanisms: Type I interferons restricted extracellular MV release, while IFN[gamma] limited neuron-to-neuron spread. These findings will enable us to better understand the cell-specific responses to interferons induced by viral infection, and will elucidate how interferons function in the unique environment of the CNS.
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Details
- Title
- Interferons Induce BST-2/tetherin in Measles Virus-Infected Neurons and Permissive Mice
- Creators
- Alicia Marie Holmgren
- Contributors
- Glenn Rall (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 113 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970223804721