Date of Award

2019

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

Abstract

Coxsackievirus type B (CVB3) is one of the six serotypes of the Coxsackievirus family of non-enveloped, linear, and positive-sense single-stranded RNA viruses. It is a pathogenic enterovirus that belongs to the same genus as the notable pathogen poliovirus. CVB3 can cause a range of illnesses from a fever to gastrointestinal distress but is most noteworthy for the ability to cause viral myocarditis, a swelling of the heart muscle. Coxsackievirus, like all RNA viruses, tends to develop mutations rapidly due to its error prone polymerase and lack of proofreading activity. These mutations can be advantageous for the virus, allowing it to develop traits that enhance replication and pathogenesis. Due to its major clinical importance and a lack of available vaccine and antivirals, there is an impetus to identify effective antivirals against CVB3. In that regard, the virus' ability to mutate poses a major obstacle to successful antiviral treatment and must be explored further to better understand the mechanisms of antiviral resistance and improve drug development.Polyamines are small positively charged molecules that are present in all cells and have crucial roles in processes such as transcription, translation, DNA replication and signaling. They are also fundamental to a virus' ability to infect a host. When drugs that diminish polyamines are added to cells, the virus' ability to replicate tapers. One drug that acts in this way is difluoromethylornithine (DFMO), which diminishes the production of polyamines by inhibiting the first step in polyamine synthesis: the conversion of ornithine to putrescine. In order to better understand how CVB3 could evolve resistance to antiviral treatments, CVB3 was seriallypassaged in the presence of DFMO. The resultant mutations that arose in CVB3 may correlate with its ability to infect a host who is undergoing antiviral therapy.Passaging CVB3 in the presence of DFMO illuminated 3 mutations: VP3- 234R, which is a site in the viral capsid; 2A- Q29K and 3C- Q52R both of which are sites in viral proteases. These proteases are crucial for multiple stages of infection including protein processing and packaging. Due to the vital importance of the viral proteases, these mutations and their seeming tie with polyamines, the focus of this study will revolve around these mutations. From these initial findings, we hypothesize that polyamines modulate viral protease activity and CVB3 gains resistance to polyamine depletion via mutation of its protease(s).

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