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Characterization of a repurposed antiviral for HSV-1 in Neural Progenitor Cells and Organoid models

MURALIDARAN, VAISHALI (2021) Characterization of a repurposed antiviral for HSV-1 in Neural Progenitor Cells and Organoid models. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Herpes Simplex virus 1 (HSV-1) infection is a debilitating illness and can lead to severe complications such as encephalitis and keratitis if untreated. The global seropositivity rate of this virus in the population (ages 0 to 49) is 66.6%, making it a public health concern worldwide. The high prevalence of this disease makes the discovery of new treatments for HSV-1 essential. The “gold standard” antiviral, acyclovir, is a highly efficacious treatment for HSV-1 infection, however, prolonged use may lead to the development of strains of acyclovir-resistant HSV-1. These acyclovir-resistant strains have a greater potential to lead to complications especially in immunocompromised individuals, thus making the discovery of new antivirals paramount. There is an urgent need to identify novel anti-herpetic drugs that can inhibit acyclovir-resistant HSV-1 strains.
Herein, we describe a computational method of drug repurposing to elicit potential new antivirals for HSV-1. This method was executed by utilizing transcriptomic data from neurons as input data to a database known as BaseSpace Correlation Engine (Illumina®) to generate a list of correlated pharmacological compounds. This list was then manually filtered to select one compound that was positively correlated (Retinoic acid) and supported the host immune system. Retinoic acid was tested in both 2D (Neural Progenitor cells) and 3D (organoid models) and resulted in no change in the presence of HSV-1 with an MOI of 0.1 in 02SF 2D cultures post-HSV-1 infection. Retinoic acid testing on 01SD-derived organoid model sections also showed differences with regard to activity when compared to 02SF-derived organoid model sections, as a decreased prevalence of virus was observed in 01SD-derived organoid model sections.
We also observed variability in the activity of Retinoic acid post-HSV-1 infection between previous literature on Vero cells and our data from Neural Progenitor cells. HSV-1 is a neurotropic virus and our results demonstrated that Neural Progenitor cells (NPCs) and brain organoid models did not show a decrease in prevalence of HSV-1 post Retinoic acid treatment. Thus, this dissertation demonstrates that several factors should be considered while testing drug candidates' antiviral activity in vitro, especially the importance of the utilization of disease-relevant cell types.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
MURALIDARAN, VAISHALIvam62@pitt.eduvam62
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNimgaonkar, VishwajitVishwajitNL@upmc.edunimga
Committee MemberDemirci, Yesimfyd1@pitt.edufyd1
Committee MemberUrban, Zsolturbanz@pitt.eduurbanz
Committee MemberD'Aiuto, Leonardodaiutol@upmc.eduled34
Date: 12 May 2021
Date Type: Publication
Defense Date: 16 April 2021
Approval Date: 12 May 2021
Submission Date: 29 April 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 98
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: HSV-1, Organoids, Cell biology, Virology, Correlation Analysis
Date Deposited: 13 May 2021 02:50
Last Modified: 13 May 2021 02:50
URI: http://d-scholarship.pitt.edu/id/eprint/40908

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