Author ORCID Identifier

0000-0002-1258-4811

Date of Award

5-14-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Markus Germann

Second Advisor

Margo Brinton

Third Advisor

Gregory Poon

Fourth Advisor

W. David Wilson

Abstract

All viruses are dependent on interactions with host cellular proteins to perpetuate their lifecycles. The genus Flavivirus, one of the four genera that comprise the family Flaviviridae, contains members that cause significant morbidity and mortality worldwide. Among the mosquito-transmitted flaviviruses, West Nile Virus (WNV), dengue (DENV), and Zika virus (ZIKV) have emerged in the Western hemisphere, which now joins Southeastern Asia and Africa as an endemic region. There are no effective antiviral therapies for treating individuals with flavivirus infections, and only a few flavivirus vaccines are available for humans.

Current knowledge about the complex mechanisms that differentially regulate flavivirus positive and negative strand RNA synthesis during the various stages of the replication cycle is incomplete. Previous work identified a multi-contact site interaction between the cell protein eEF1A and the conserved flavivirus 3′(+)SL RNA as well as an interaction between the cell protein TIAR and the viral 3′(-)SL RNA. Both of these interactions have been shown to affect viral replication.

The formation of TIAR-RNA complexes was studied using a number of biochemical and analytical chemistry techniques. Further studies were performed to examine TIAR complex formation in the context of the 3′(-) WNV SL. Finally, a structural analysis of EF1A1 was preformed using a deposited cryo-EM structure. Ultimately, elucidating the structures and functions of these host cellular protein-viral RNA complexes is essential for fully understanding flavivirus replication cycles and for the future rational design of broad spectrum anti-flavivirus therapies.

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Available for download on Tuesday, April 26, 2022

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