Viral myocarditis may be caused by a number of different viruses, and the mechanisms of pathogenicity can be both immune mediated and/or due to direct cytopathic effect. While extensive research has been done regarding immune-mediated mechanisms, the mechanisms of direct cytopathic effect remain largely unexplored. Reovirus induced murine myocarditis is not immune mediated, providing for an excellent disease model. Reovirus induction of, and sensitivity to, interferon-beta (IFN-ß) has previously been found to be an important determinant for protection against viral myocarditis. There are many interferon regulatory factors that can both regulate, and be regulated by, IFN-ß. In the first part of this dissertation, transient transfections of primary cardiac myocyte cultures (PCMCs) were used to investigate the role of interferon regulatory factor-1 (IRF-1) in regulation of IFN-ß. We found that while IRF-1 is downstream of the IFN response, it still plays an important protective role against viral myocarditis. In the next chapter, reovirus induction of Interferon Stimulated Genes (ISGs) was investigated in PCMCs and compared with a more generalized cell type, primary murine embryonic fibroblasts (PMEFs). Here we found that reovirus induction of ISGs is cell type-specific and interferon-mediated, yet levels of induction are discordant with viral induction of IFN. These results suggested that cell types that are prone to induction of IFN are resistant to induction of ISGs. In appendix I, reovirus induction of an Interferon Stimulated Response Element (ISRE) was investigated in the above mentioned cell types, providing insight into reovirus induction of ISGs and the cell type-specific response. In appendix II, the effect of IRF-1 on ISG induction was further examined by overexpressing IRF-1. These data indicated that IRF-1 could regulate ISGs and ISRE sequences, but that IFN may induce or activate a product that inhibits IRF-1 induction of these genes. In the final appendix, reovirus induction of the ISG, IRF-7, was investigated in PCMCs and PMEFs using real-time PCR. Here, we found that reovirus induction of IRF-7 is discordant with reovirus induction of IFN. Possible mechanisms of differential ISG induction are discussed in the summary of this dissertation to provide an overall picture of the cardiac IFN response to virus infection.
| Identifer | oai:union.ndltd.org:NCSU/oai:NCSU:etd-06232003-131502 |
| Date | 26 June 2003 |
| Creators | Smoak, Kathleen Azzam |
| Contributors | Dr. Barbara Sherry, Dr. Tim Petty, Dr. Scott Laster, Dr. Stephen Libby |
| Publisher | NCSU |
| Source Sets | North Carolina State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://www.lib.ncsu.edu/theses/available/etd-06232003-131502/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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