Date of Award

1-1-2019

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biological Sciences

Content Description

1 online resource (xiv, 281 pages) : illustrations (some color)

Dissertation/Thesis Chair

Cara T Pager

Committee Members

Douglas Conklin, Paolo Forni, Gabriele Fuchs, Ing-Nang Wang

Keywords

G3BP1, HuR, stress graules, Zika virus, Zika virus infection, RNA-protein interactions, Protein binding

Subject Categories

Biology | Virology

Abstract

Globalization and climate change have contributed to the rampant spread of mosquitos from tropical and subtropical climates into more moderate climates, and thus also the spread of a number of vector-borne viruses. As of 2016, the World Health Organization (WHO) estimates that of all human infections world-wide, 16% result from vectors such as flies, ticks, and mosquitos. The spread of such viruses has encouraged expedient evolutionary pressures resulting in more pathogenic viruses that continually pose a serious threat to public health. First discovered in 1947, Zika virus (ZIKV) has only recently presented as a detriment to public health. The importance of how this virus interacts with the infected individual, propagates through out the body, and causes neurological complications are crucial understandings required for developing more targeted treatments. In probing the dynamics and interactions of stress granule components as they relate to ZIKV infection, we determined G3BP1 and HuR act in contrasting fashion during infection. Both play vital roles during replication of the ZIKV genome as determined by reporter assays and isolation of viral replication complexes. Moreover, the antiviral properties HuR exhibited against ZIKV were unexpected as this protein acts in a proviral manner for similar viruses. Interestingly, HuR belongs to a family of four proteins of which expression is restricted to neuronal tissues. Using available next-generation sequencing data, a model was created to articulate a potential mechanism by which the currently circulating strain of ZIKV results in neurological maladies. This model led to the hypothesis that neuronal- specific RNA binding proteins play essential antiviral roles in the developing fetal brain. Of the four Hu proteins, the ubiquitously expressed HuR is the most understood, while a significant amount of work has detailed the role HuB and HuD play in the nervous system. In comparison, very little is known about HuC though the neuronal Hu proteins share a very high degree of sequence homology. In summation, the research presented within this thesis details the intimate interactions between virus and host that many pathogens depend on. Additionally, the work alludes to a new avenue of research focussed on viral-host interactions during neuronal development.

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