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Investigating the hepatitis C virus and dengue virus interactions with host lipid pathways : from circulating human microRNAs to lipid modulating agents

University of British Columbia

Cholesterol and lipid levels are maintained through tightly controlled and complex feedback mechanisms that involve regulation of major metabolic genes. Dysregulation of cellular or plasma lipid levels can lead to a wide range of pathologies, including hyperlipidemia, atherosclerosis and other disorders. A number of viruses, including important human viruses of the Flaviviridae family such as hepatitis C virus (HCV) and dengue virus (DENV), utilize and modulate host lipids to support their lifecycles, and the resulting changes in lipid metabolism may contribute to virus-associated pathologies. The overall aim of this thesis was to determine the role of key regulators of host lipid homeostasis, including microRNAs (miR-122, miR-24 and miR-223) and proprotein convertases (SKI-1/S1P and PCSK9) during viral infection and virus-associated disease. To address this aim, we first examined the molecular interplay between three circulating microRNAs known to act as regulators of lipid homeostasis. The data we present in Chapter 2 shows that specific signatures of the three microRNAs were associated with different treatment outcomes in patients with chronic hepatitis C (CHC), indicating that these microRNAs correlate with HCV infection. We then tested the hypothesis that enzymatic regulators of lipid metabolism could also indicate HCV infection, and in Chapter 3 we show that PCSK9 levels were significantly upregulated in patients who achieved a treatment-based viral cure but not in relapsers. These data indicate that changes in PCSK9 concentrations may have an important role in both HCV infection and in host lipid metabolism. In Chapter 4, we tested whether reducing the abundance of lipid droplets via inhibition of SKI-1/S1P with a small molecule PF-429242 suppresses DENV infection. The inhibitor blocked SKI-1/S1P-mediated accumulation of lipid droplets in hepatoma cells and reduced DENV infection, identifying SKI-1/S1P as a potential target for indirect-acting anti-DENV agents. This study on modulators of lipid metabolism during HCV and DENV infections provides new insights into the complex host-virus interactions that associate with virally-induced disease. We hope that our data lay the foundation for understanding disease pathogenesis and support the development of future strategies for Flaviviridae - associated diseases.

Text

2017-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/60214

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/