EFFECT OF MEMBRANE COMPOSITION ON VIRAL ENTRY AND EGRESS

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Abstract

Enveloped viruses rely heavily on their ability to merge the viral membrane to the host cell membrane during viral entry. Therefore, improving the understanding of membrane components utilized in viral fusion is crucial. Additionally, the development of broad-spectrum antivirals capable of inhibiting the entry of zoonotic viruses that cause a tremendous burden to human health is critically important. Nipah virus is a deadly enveloped virus with a high mortality rate in humans and agriculturally important animals. Despite the high case-fatality rates of the Nipah virus and many other enveloped viruses (i.e., Ebola, SARS, MERS), there is a lack of approved antiviral therapeutics. Various chemical agents capable of altering the viral membrane composition have revealed a valuable target in antiviral drug design. Therefore, studying the role of viral membrane components is vital in understanding fusion mechanics and for the development of potential antivirals. Herein, I present a series of experiments used to study virus-induced membrane fusion. First, to understand the role of membrane cholesterol in Nipah virus fusion and egress, I performed various biochemical assays that revealed that membrane cholesterol influences the levels of virus-cell and cell-cell membrane fusion. Second, I found that modulating the concentration of membrane cholesterol alters both the incorporation of Nipah virus proteins into lipid rafts and the budding efficiency of Nipah virus-like particles. Lastly, we characterized a novel class of broad-spectrum antivirals, the XM series, aimed at inhibiting viral membrane fusion. We found that XM-01 increases order in the viral membrane, which significantly reduced or completely inhibited viral entry. These inhibitors can cause various enveloped viruses to be fusogenically inert while leaving immunogenic sites intact. This effect allowed us to test the ability of these compounds to produce inactivated-virus vaccines, tested for the Influenza virus. Altogether, these findings progress the understanding of membrane components in viral entry and release, and the development of effective antivirals.

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246 pages
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2020-05
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antiviral; cholesterol; glycan; membrane fusion; viral egress; viral entry
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Aguilar-Carreno, Hector
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Daniel, Susan
VanderVen, Brian
Whittaker, Gary
Degree Discipline
Biomedical and Biological Sciences
Degree Name
Ph. D., Biomedical and Biological Sciences
Degree Level
Doctor of Philosophy
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Government Document
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dissertation or thesis
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