Date of Award

Summer 7-12-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Dr. Christopher F. Basler

Second Advisor

Dr. Richard Plemper

Third Advisor

Dr. Margo Brinton

Abstract

Novel emerging zoonotic viruses are of significant public health concern due to a lack of treatment options and the required to achieve pharmaceutical development.

Coronaviruses, a family of positive-sense RNA viruses, have spilled over from their animal hosts into the human population. Most notably, is the recent emergence of SARS-CoV-2 that has caused a multi-year global pandemic, nearing a billion cases worldwide. Coronaviruses rely on host membranes for entry, establishment of replication centers, and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. In chapter one we show that compounds targeting VPS34 and fatty-acid metabolism exhibit potent inhibition of SARS-CoV-2. Mechanistic studies with compounds targeting multiple steps up- and down-stream of fatty acid synthase (FASN) identified triacylglycerol production and protein palmitoylation as requirements for viral RNA synthesis and infectious virus production. Further, FASN knockout results in significantly impaired SARS-CoV-2 replication that can be rescued with fatty-acid supplementation. These observations identify fatty-acid metabolism as a promising target for novel SARS-CoV-2 therapeutic development.

Filoviruses are a family of zoonotic negative-sense RNA viruses known to cause severe and fatal disease in humans. The growing number of novel filoviruses being discovered have caused speculation over whether or not they are capable of causing productive human disease. A determining factor of virulence is the ability of viral proteins to antagonize host immune defenses to promote infection. Chapter two characterizes the VP35, VP40, and VP24 proteins of the newly identified Měnglà virus (MLAV) for their ability to regulate the interferon response in human and bat cells, as compared to their Ebola (EBOV) and Marburg (MARV) counterparts. MLAV VP35 and VP40 inhibited type I IFN responses, consistent with the activity of their homologues. MLAV VP40 inhibited IFN production and signaling by unlinked mechanisms. MLAV VP24 did not inhibit IFN gene expression or activate an antioxidant response, functions of EBOV and MARV, respectively. These functional observations support placement of MLAV in a distinct genus and provide insight into potential novel host-interactions that provide value for future filovirus antiviral development.

DOI

https://doi.org/10.57709/23985062

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