Date of Award

Spring 5-3-2024

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Master of Science (MS)

Department

Microbiology

Advisor

Melissa Maginnis

Second Committee Member

Melody Neely

Third Committee Member

Julie Gosse

Abstract

JC Polyomavirus (JCPyV) infects the majority of the population and initially establishes a persistent but asymptomatic infection of the kidneys. In healthy individuals the infection remains controlled by the host immune system, but for individuals experiencing prolonged immunosuppression the infection can reactivate and spread to the brain where it causes progressive multifocal leukoencephalopathy (PML), a fatal neurodegenerative disease. Currently there are no approved therapies to treat PML and affected individuals suffer rapid motor weakness and cognitive deterioration. To identify novel antiviral treatments for JCPyV infection, therapeutic hits of a large-scale drug screen recently published by our lab were explored. Drugs in the receptor agonists/antagonists category were of particular interest given the important role of the serotonin 5-hydroxytryptamine (5-HT2) receptor during JCPyV internalization. Seven drugs identified in the screen and two additional therapeutics known to inhibit infection of related viruses were assessed for their ability to reduce JCPyV infection. Drugs were validated using infectivity assays, and the mechanism of inhibition was further explored. Three drugs, histamine H1 receptor antagonist cetirizine, 5-HT1B receptor agonis 5-nonyloxytrptamine (5NT), and GRK2 inhibitor paroxetine, significantly reduced infection of JCPyV. Additionally, paroxetine specifically reduced host cell receptor signaling and viral internalization. These findings highlight the potential of receptor signaling and viral entry mechanisms as possible targets for antiviral drug development. Further, this research suggests that FDA-approved receptor agonists/antagonists currently used to treat other medical conditions could be repurposed into antivirals for the possible treatment of JCPyV infection and the fatal disease it causes.

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Available for download on Tuesday, July 01, 2025

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