Date of Award

4-30-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

First Advisor

Bryan Mounce

Second Advisor

Susan Uprichard

Abstract

Polyamines are a class of metabolites consisting of small carbon chains that contain amine groups and are positively charged at cellular pH. They play many important roles within the cell and are necessary for cell growth, membrane function, transcription, and translation. They are also required by a myriad of viruses for a productive infection. This includes the non-polio enterovirus Coxsackievirus B3 (CVB3). CVB3 is a cardiotropic virus that can readily infect the heart and cause irreversible damage which can eventually lead to dilated cardiomyopathy and the need for a heart transplant. Unfortunately, there are no approved antivirals or vaccines that target CVB3. CVB3 infection requires polyamines at multiple stages of infection, including binding and polyprotein processing. However, the underlying mechanisms that polyamines played during CVB3 infection were unknown. Cholesterol is another important metabolite required by CVB3 for both binding and replication. Interestingly, depletion of polyamines in animal models results in reduced serum cholesterol levels. Due to this, we proposed that polyamines’ underlying influence on cholesterol synthesis impacts CVB3 at multiple stages of infection. This study found that depletion of polyamines in cells treated with the FDA approved drug DFMO significantly decreases cholesterol biosynthesis. This is due to the global cholesterol transcription factor, SREBP2, indirectly requiring polyamines for its translation through a processes called hypusination. Polyamines’ role in hypusination, and thus cholesterol synthesis, is required for CVB3 to bind and enter cells as well as efficiently replicate through the formation of replication organelles. This study shows a novel connection between two metabolic pathways previously thought to be distinct and how this connection is required for CVB3 infection.

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