Date of Award
12-16-2019
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biology
First Advisor
Charlese Garnett-Benson
Second Advisor
Margo Brinton
Third Advisor
Casonya Johnson
Abstract
Adenovirus (AdV) infection is ubiquitous in the human population and causes acute infection in the respiratory and gastrointestinal tracts. In addition to lytic infections in epithelial cells, AdV can persist in a latent form in mucosal lymphocytes, and nearly 80% of children contain viral DNA in the lymphocytes of their tonsils and adenoids. Reactivation of latent AdV is thought to be the source of deadly viremia in pediatric transplant patients. Adenovirus latency and reactivation in lymphocytes is not well-studied, though immune cell activation has been reported to promote productive infection from latency. In lymphocytes, programs of gene expression during both resting and activated states have been shown to be regulated in part by chromatin remodelers and co-repressors, including Class I and II histone deacetylases (HDACs), Class III HDACs (sirtuins), and the C-terminal Binding Protein Family (CtBPs). Because the adenovirus genome is chromatinized through rapid association with cellular histones upon entry into the host cell nucleus, viral gene expression is potentially regulated by these same cellular chromatin-modifying mechanisms and responsive to immunoactivation of the host lymphocyte. In this doctoral work, we show that enzymatic activity of Class I HDACs and sirtuins, but not Class II HDACs, contribute to the repression of viral early and late genes during persistent infection. We also show that modulation of cellular NAD+/NADH can de-repress adenovirus gene expression in persistently-infected lymphocytes. In contrast, disrupting the NAD-dependent CtBP repressor complex interaction with PxDLS-containing binding partners paradoxically alters AdV gene expression.
DOI
https://doi.org/10.57709/15903089
Recommended Citation
Dickherber, Megan, "Histone Deacetylase-linked Repression and Metabolically-linked Derepression of Adenovirus Persistent Infection of Lymphocytes." Dissertation, Georgia State University, 2019.
doi: https://doi.org/10.57709/15903089
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