Guedon, Jean-Marc
(2014)
New Insights and Treatments For VZV-induced Pain In a Rat Model of Postherpetic Neuralgia.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Varicella Zoster Virus is the causative agent of varicella (chickenpox) upon primary infection and zoster (shingles) upon reactivation from latency. Viral reactivation causes neurological complications, with pain being the most common. Almost all zoster patients are prescribed medication to alleviate pain and up to one third will develop a chronic pain state that lasts longer than 30-90 days known as Post-Herpetic Neuralgia (PHN). A majority of these PHN patients describe pain in one of three ways: a constant burning, intermittent stabbing or shooting, and lastly allodynia (pain from normally innocuous stimuli), which is the most common and debilitating. A rat model of VZV-induced pain was established in 1999 which mimics the pain seen in humans. The goal of this thesis is to utilize the rat model of VZV-induced pain to characterize the viral effects on the host, investigate mechanisms that result in chronic hypersensitivity, and to evaluate novel treatment strategies. We have discovered that viral infection of rat tissue ex vivo is limited, viral DNA persists at low levels early in infection, and viral RNA transcription is limited to immediate early and early expressed genes. We investigated host changes upon VZV infection which include a decrease in peripheral neurite innervation density and changes in whole dorsal root ganglia transciption with up-regulation of 86 genes and down-regulation of 114 host genes. We show that ORF47, a viral protein kinase, is both necessary and sufficient for the induction of hypersensitivity in rats, and this effect may be related to its phosphorylation of ORF9, an essential tegument associated protein. Interestingly, ORF47 may not be the only VZV protein involved in the induction of hypersensitivity, as animals transduced with an HSV vector expressing IE62 also develop hypersensitivity to mechanical stimuli, suggesting a role for IE62 in VZV-induced pain. Lastly, we tested novel herpes simplex vectors that express pain relieving genes for their efficacy on VZV-induced pain. Vectors delivering human preproenkephalin, an endogenous opioid peptide, and soluble TNFα receptor alleviate hypersensitivity in our model. The rat model has enabled us to better understand and treat VZV-induced pain.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
12 December 2014 |
| Date Type: |
Publication |
| Defense Date: |
4 December 2014 |
| Approval Date: |
12 December 2014 |
| Submission Date: |
12 December 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
152 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Virology and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Varicella Zoster Virus, Pain, Hypersensitivity, Postherpetic Neuralgia, Rodent model, Gene Therapy, HSV vector |
| Date Deposited: |
12 Dec 2014 20:03 |
| Last Modified: |
15 Nov 2016 14:26 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/23851 |
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