Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Sara R. Cherry

Second Advisor

Jorge Henao-Mejia

Abstract

Mosquito-borne viruses represent a substantial public health threat capable of causing severe, endemic disease often with few therapeutic options. To control viral replication, host cells rely on innate intracellular immune pathways including the Type I interferon (IFN) response. However, many viruses have adapted potent mechanisms to antagonize these classical antiviral pathways. To survive, the host has evolved alternative counterdefense strategies to inhibit viral replication. A growing body of evidence has recently shown that long noncoding RNAs (lncRNAs) play important roles in regulating innate immunity. Whether lncRNAs can also contribute to complementary antiviral defense and counterdefense responses is unclear. Using high-throughput, loss-of-function, RNAi screening, we identified two new antiviral lncRNAs: ALPHA and HAGLR. We found that ALPHA directly interacts with chikungunya virus (CHIKV) genomic RNA and impacts viral RNA replication independently of IFN-dependent signaling. These results are discussed in Chapter 2. In parallel, we also investigated the antiviral function of the conserved, endothelial cell-specific lncRNA HAGLR both in vitro and in vivo. These findings are discussed in Chapter 3. Together, these data demonstrate that lncRNAs can serve as potent antiviral effectors in a virus- and context-specific manner, adding another layer to our understanding of antiviral defense.

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