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    HCMV Manipulation of Host Cholesteryl Ester Metabolism

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    Author
    Dahlmann, Elizabeth Alan
    Issue Date
    2019
    Keywords
    Cholesteryl Ester
    HCMV
    Lipidomics
    SOAT1
    Advisor
    Goodrum, Felicia
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release after 01/22/2021
    Abstract
    Human cytomegalovirus (HCMV) is a β-herpesvirus that infects over 50% of people above the age of 40. Once infected, HCMV establishes a lifelong latent infection with periodic reactivation. Most infections are asymptomatic. However, infection in immunocompromised patients may result in fatal HCMV-related complications. Further, congenitally-acquired HCMV infection is the leading cause of birth defects in the United States. The HCMV virion contains a large double-stranded DNA genome encapsidated by a protein shell that is surrounded by a lipid membrane. Like all enveloped viruses, HCMV steals host lipids to generate its envelope membrane. While previous studies demonstrate that HCMV replication requires lipid metabolism, the details of virally-induced lipid changes remain poorly defined. We performed an untargeted lipidomic screen using liquid chromatography high resolution tandem mass spectrometry to identify and quantitatively measure how infection alters the lipidome of cells. We found that HCMV increases cholesteryl esters (CE) by 24 hours post infection. CE lipids are synthesized by sterol O-acyltransferase 1 (SOAT1) attaching a fatty acyl-CoA to a cholesterol molecule. I hypothesized that early stages of HCMV replication induce CE biosynthesis and that CE are required for viral replication. In support of our hypothesis, we found HCMV induces SOAT1 gene expression. Further, HCMV immediate early pUL37x1 is partially responsible for virally-induced CE accumulation. We found that treating infected cells with a SOAT1 inhibitor blocked CE production and infection. Overall, our findings suggest that HCMV induces CE synthesis that can be targeted to block infection.
    Type
    text
    Electronic Thesis
    Degree Name
    M.S.
    Degree Level
    masters
    Degree Program
    Graduate College
    Immunobiology
    Degree Grantor
    University of Arizona
    Collections
    Master's Theses

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