HOST FACTOR-DIRECTED INHIBITION OF LATE SARS-COV-2 LIFE CYCLE STAGES
AdvisorFrieman, Matthew B.
MetadataShow full item record
AbstractThe sudden emergence of Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus Disease 2019 (COVID-19), burgeoned into a multi-year pandemic that continues to test the world’s healthcare systems and economies. Early therapeutic development led to multiple compounds that target early stages of the SARS-CoV-2 lifecycle with varying degrees of efficacy: monoclonal antibodies (e.g., Casirivimab, Tixagevimab) to block virus entry; protease inhibitors (e.g., Paxlovid) to block proteolytic cleavage of nonstructural proteins translated shortly after viral entry; and nucleoside analogues (e.g., Molnupiravir) to block viral RNA replication. However, later stages of the SARS-CoV-2 life cycle are relatively understudied and, consequently, late-stage inhibitors that could prove more effective or work synergistically with early-stage inhibitors are lacking. This dissertation work describes two host proteins that inhibit later SARS-CoV-2 lifecycle stages when modulated. PIKfyve inhibition was shown to block late lifecycle stages of SARS-CoV-2, in addition to broadly inhibiting early and middle stages, but exacerbated disease in a COVID-19 mouse model. Overexpression of the interferon stimulated gene 2’,3’-cyclic-nucleotide-phosphodiesterase (CNP) in vitro was shown to inhibit virion assembly by blocking SARS-CoV-2-induced mitochondrial depolarization and reactive oxygen species release. Additionally, overexpression of CNP in Balb/c laboratory mouse lungs reduced SARS-CoV-2 titers to undetectable levels at 2- and 4-dpi. Importantly, this work has identified host factors that could be further developed into therapeutic targets.
DescriptionMolecular Microbiology and Immunology
University of Maryland at Baltimore
University of Maryland, Baltimore, School of Medicine, Ph.D., 2023