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Identifying Varicella-Zoster Virus Latent Genomes in an Alternative Neuronal Latency Model

Yee, Michael B. (2020) Identifying Varicella-Zoster Virus Latent Genomes in an Alternative Neuronal Latency Model. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Varicella zoster virus (VZV) is the etiologic agent of chickenpox (varicella) upon primary infection and shingles (herpes zoster, HZ) upon reactivation from neuronal latency. Shingles is a debilitating disease of the elderly and immune impaired that is frequently complicated. Reactivation of VZV causing HZ is painful and can result in a chronic pain state known as postherpetic neuralgia (PHN) that is difficult to alleviate. HZ has also been linked to encephalitis, meningitis, vasculopathies and increased risk of stroke, all of which emphasize the continued public health demand for better treatments and/or vaccines. VZV latency and reactivation has not been well characterized because it presents monumental difficulties studying it in a laboratory setting. Its human-specific restriction requires human neuronal platforms for modeling neurotropism, latency and reactivation. Importantly, VZV genomes are found not only in neurons of sensory ganglia, but in those of autonomic, enteric and cranial ganglia, and possibly even the CNS. These latent genomes are difficult to characterize and are usually found only by performing end-stage methods of analyses, when tissues/cells need to be fixed or extracted. One aspect of this research was to explore methods that would better enable the identification of VZV genomes in latently infected cells and whether they could be applied in a live-cell in vitro setting. We have previously established that sensory-like neurons derived from human embryonic stem cells (hESC) can host both a productive VZV infection and a model state of VZV latency that can be experimentally reactivated. However, the maintenance of hESCs and their differentiation into sensory neurons for larger scale applications is exceedingly demanding. The second goal of this research was to evaluate an alternative neuron-like system that is more easily expandable for large-scale applications. We evaluated the proliferative human neuronal precursor cell line Lund human mesencephalic (LUHMES) cells. Differentiated LUHMES can easily be scaled to large numbers and show biochemical, morphological, and functional features of mature neurons. While both undifferentiated and differentiated LUHMES cells are fully permissive to VZV infection, current studies are addressing the potential of this system to host a VZV latent state, and whether this is experimentally reactivatable.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Yee, Michael B.mby1@pitt.edumby10000-0002-6296-7757
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorKinchington, Paul R.kinchingtonp@upmc.edukinch0000-0002-1901-9970
Committee MemberNimgaonkar, Vishwajit L.vishwajitnl@upmc.edunimga
Committee MemberRappocciolo, Giovannagiovanna@pitt.edugiovanna
Date: 30 July 2020
Date Type: Publication
Defense Date: 31 March 2020
Approval Date: 30 July 2020
Submission Date: 21 November 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 71
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: VZV, virus, neuron model, latency, reactivation, LUHMES
Date Deposited: 30 Jul 2020 21:11
Last Modified: 30 Jul 2020 21:11
URI: http://d-scholarship.pitt.edu/id/eprint/37864

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