Date of Award

Spring 8-28-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Sara L. Sawyer

Second Advisor

Robin D. Dowell

Third Advisor

Roy Parker

Fourth Advisor

Kristi S. Anseth

Fifth Advisor

Robert L. Garcea

Abstract

Patterns in nature, many going unnoticed, are a defining characteristic of life. In this thesis, I will describe four studies that I have completed during my doctoral work. These will highlight how both host immune system and viral pathogens harness non-random biological patterns to aid in immunity or increase pathogenicity, respectively. Chapter 2 will describe the evolutionary history of a component of the primate innate immune system, Schlafen11, and its involvement in the defense against viruses. I attempt to show that Schlafen11 takes advantage of the pattern of non-optimal codon usage of HIV-1 transcripts in order to inhibit viral replication. In Chapter 3, I will further expand on this story, showing that the mechanism of action of Schlafen11, as well as a related paralog Schlafen12L, targets viral transcripts during translation. Schlafens appear to act in a mechanism akin to No-go decay, where transcripts that are translated inefficiently---inducing ribosomal pausing---appear to be targeted for degradation by Schlafen11 and Schlafen12L. This No-go-like mechanism extends beyond just viral transcripts insofar that host transcripts that are predicted to be translated inefficiently are also targeted for degradation by these Schlafens. In Chapter 4, I turn to studying how the dengue virus protease recognizes and cleaves specific 8-amino acid peptide motifs of host proteins in order to restructure the cellular environment to aid in viral replication. Finally, in Chapter 5, I describe a specific instance in which the dengue virus protease may have influenced the evolution of a protein involved in the innate immune response against dengue, the STimulator of INterferon Genes (STING).

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