acase@tulane.edu / Herpesviruses depend on subverting or harnessing the metabolic state and molecular machinery of the infected host cell for viral replication. Human cytomegalovirus (HCMV) was one of the first viruses to have virally-induced host cell metabolic changes investigated during infection and remains one of the better explored viruses in this area of research. In this thesis, I investigate whether HCMV infection impacts mitochondrial respiration, a metabolic pathway that has yet to be fully explored during infection. In Chapter 2, I explore the impact of HCMV replication on mitochondrial metabolism and observe that HCMV infection markedly increases respiration. I show that concomitant with the increase in mitochondrial function HCMV increases mitochondrial biogenesis and determine that functional mitochondrial respiration is required for efficient HCMV replication. In Chapter 3, we examine whether the pharmacological agent, metformin, is capable of inhibiting HCMV replication through inhibition of Complex I and subsequent inhibition of mitochondrial respiration. I show metformin is capable of inhibiting efficient HCMV replication during viral early gene expression and that this effect is neither strain nor species specific and is not mediated by cell death. However, this inhibition is sensitive to excess glucose within the media. I demonstrate that metformin is capable of inhibiting mitochondrial respiration even in glucose-excess media and that inhibition of HCMV replication is linked mechanistically to inhibition of mitochondrial respiration. The results from this study reveal how HCMV affects mitochondrial respiration during infection and add to the broader understanding of the impact of HCMV infection impact on host cell metabolism. Further, these studies provide evidence that specific metabolic inhibitors may effectively, and potentially safely, target HCMV infection. / 1 / Joseph A. Combs
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_83293 |
| Date | January 2018 |
| Contributors | Combs, Joseph (author), Morris, Cindy (Thesis advisor), School of Medicine Biomedical Sciences Graduate Program (Degree granting institution) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic, pages: 195 |
| Rights | No embargo, Copyright is in accordance with U.S. Copyright law. |
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