Browsing by Author "Mody, Prapti"
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Item Herpes simplex virus: A versatile tool for insights into evolution, gene delivery, and tumor immunotherapy(Sage, 2020-05-29) Spencer, Juliet; Mody, Prapti; Pathak, Sushila; Hanson, Laura K.Herpesviruses are prevalent throughout the animal kingdom, and they have coexisted and coevolved along with their host species for millions of years. Herpesviruses carry a large (120-230 kb) double-stranded DNA genome surrounded by a protein capsid, a tegument layer consisting of viral and host proteins, and a lipid bilayer envelope with surface glycoproteins. A key characteristic of these viruses is their ability to enter a latent state following primary infection, allowing them to evade the host’s immune system and persist permanently. Herpesviruses can reactivate from their dormant state, usually during times of stress or when the host’s immune responses are impaired. While herpesviruses can cause complications with severe disease in immune-compromised people, most of the population experiences few ill effects from herpesvirus infections. Indeed, herpes simplex virus 1 (HSV-1) in particular has several features that make it an attractive tool for therapeutic gene delivery. Herpes simplex virus 1 targets and infects specific cell types, such as epithelial cells and neurons. The HSV-1 genome can also accommodate large insertions of up to 14 kb. The HSV-1-based vectors have already achieved success for the oncolytic treatment of melanoma. In addition to serving as a vehicle for therapeutic gene delivery and targeted cell lysis, comparative genomics of herpesviruses HSV-1 and 2 has revealed valuable information about the evolutionary history of both viruses and their hosts. This review focuses on the adaptability of HSV-1 as an instrument for gene delivery and an evolutionary marker. Overall, HSV-1 shows great promise as a tool for treating human disease and studying human migration patterns, disease outbreaks, and evolution.Item Mechanisms of cytomegalovirus regulation of neurodegenerative markers(9/9/2019) Mody, Prapti; Hanson, Laura K.; Hynds, DiAnna L.Alzheimer’s disease (AD) manifests with loss of neurons associated with intercellular amyloid plaques made up of amyloid beta peptides (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau proteins. Normally, Aβ peptides function as cell signaling molecules and can mediate antimicrobial activity. Tau is one of the microtubule stabilizing proteins in cells and its expression and post-translational modifications depend upon cell type and cell age. Despite testing many therapeutics designed to target abnormal amyloid or tau, there is no sustained treatment. Current research is therefore focused on early steps in production of dysfunctional amyloid and tau11, however, there are relatively few strong established models for these studies. Previous researchers have shown that some herpesvirus infections can alter amyloid and tau in ways similar to that seen in AD. There is clinical correlation between herpesvirus infection and higher risk of AD. Herpes simplex virus 1 can interact with amyloid precursor protein (APP) and affect tau v hyperphosphorylation. Based on these findings, we hypothesized that MCMV infection could be a useful model if it similarly impacted AD markers. We found that APP was upregulated in MCMV-infected fibroblasts and viral late gene products were required. Levels of processing enzymes (secretases) and one cleavage product (Aβ42) were unchanged. The activity of β-secretase was not increased. There was no similar APP induction in RCN. Thus, CMV may have cell-type or species-based differences for effects on the amyloid pathway. Levels of total tau and tau phosphorylated at S396 were increased in MCMV-infected fibroblasts and neurons. This also required viral late gene products. There was no change in tau phosphorylation at S202 or GSK3β levels. We used lithium chloride (LiCl) to inhibit activity of GSK3. Although MCMV infection was inhibited, the banding patterns for tau and phospho-tau (S396) exhibited minor alterations when LiCl was added at the time that changes started. Thus, other kinases are more likely important. We have confirmed that MCMV can induce AD markers. This is useful for using MCMV infection in AD animal models for elucidation of early steps, promising for testing novel preventives for these changes, and for developing novel antivirals.