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UBC Theses and Dissertations

Regulating the regulators : emerging roles of cellular microRNAs during influenza A virus infection Loveday, Emma-Kate


Over the past twenty years small endogenous non-coding RNAs known as microRNAs have emerged as potent regulators of gene expression during virus infection. During influenza A virus infection the role of miRNAs and their impact on the virus lifecycle is relatively unknown. With seasonal strains that can result in annual epidemics, to newly emerging subtypes that have the potential to cause a worldwide pandemic, influenza A remains a major threat to global human health. Here we aimed to determine the role miRNAs play in the host-pathogen interactions associated with varying pathogenesis during infection with different influenza A virus strains. In Chapter 2, we tested the hypothesis that human cellular miRNA expression would vary between a low pathogenic swine-origin H1N1 influenza A virus strain and a highly pathogenic avian-origin H7N7 influenza A virus strain. Utilizing high throughput microarray analysis, we identified differentially expressed miRNA and mRNA profiles during H1N1 and H7N7 influenza A infection and found strain specific expression patterns that were associated with specific cellular pathways. One of the miRNAs identified in Chapter 2 was miR-24 that targets the proprotein convertase furin, which is responsible for cleaving the hemagglutinin glycoprotein on the surface of highly pathogenic influenza A viruses. In Chapter 3, we hypothesized that synthetic miR-24 could inhibit highly pathogenic H5N1 influenza A infection. Addition of exogenous miR-24 during H5N1 infection resulted in a significant decrease in furin mRNA expression and enzymatic activity as well as reduced infectious virus released and virus spread. In Chapter 4, we hypothesized that novel miRNAs could target the proprotein convertase furin, along with two additional human proprotein convertases: PCSK9 and SKI-1/S1P, that have significant roles during the lifecycles of other enveloped viruses. We identified a novel miRNA, miR-17, that reduced furin mRNA and enzymatic activity. Furthermore, miR-24 was shown to target PCSK9, potentially contributing to the regulation of lipid metabolism. MiRNAs are now recognized as important players during virus infections, especially during the influenza A virus lifecycle. By exploiting the targets of specific miRNAs, we have identified new potential therapeutic options that could be applied to numerous enveloped viruses.

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