Date of Award

Summer 8-16-2024

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology

Advisor

Melissa Maginnis

Second Committee Member

Julie Gosse

Third Committee Member

Melody Neely

Additional Committee Members

Sally Molloy

Clarissa Henry

Abstract

JC polyomavirus (JCPyV) infects 50-80% of the human population. In healthy individuals, JCPyV establishes a persistent, asymptomatic infection in the kidneys. In severely immunocompromised individuals, JCPyV infection can result in a fatal brain infection called progressive multifocal leukoencephalopathy (PML). PML causes a lytic infection of myelin-producing glial cells in the brain and becomes progressively debilitating, sometimes resulting in death within one year of symptom onset. There are currently no targeted, approved treatments for PML, underscoring the importance of continued research on JCPyV and PML.

To identify potential antiviral therapeutics, the Maginnis laboratory performed a large-scale drug screen using the National Institutes of Health Clinical Collection (NIH-CC), which contains FDA-approved drugs and therapeutics in various stages of clinical trials. Results demonstrated that several FDA-approved drugs from different drug classes reduce JCPyV infection and that multiple “hits” identified were drugs that target cellular calcium signaling pathways. Calcium channel blockers and related calmodulin inhibitors were further characterized by viral infectivity assays with results supporting a role for calcium signaling during JCPyV infection. Calmodulin inhibitor, trifluoperazine (TFP), resulted in a significant decrease in JCPyV infection in both transformed and primary kidney and brain cell types. Further, TFP also reduced infection of polyomaviruses BK and SV40 and the coronavirus SARS-CoV-2. Investigation into the impact of TFP on the JCPyV infectious cycle demonstrated the greatest reduction of JCPyV infection at the point of viral entry. Additional work showed that JCPyV stimulates increased intracellular calcium (Ca2+) flux at times consistent with viral entry.

Exploring pre-approved drugs is a promising and demonstrated method for repurposing therapeutics to identify potential treatments for PML and other viral diseases, and findings that Ca2+ signaling is a key player in JCPyV infection could lead to the discovery of calcium-specific antiviral therapies to treat JCPyV infection and PML.

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