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    BST-2 restricts SARS Coronavirus and is antagonized by SARS-CoV ORF7a

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    Author
    Taylor, Justin Kyle
    Advisor
    Frieman, Matthew B.
    Date
    2014
    Type
    dissertation
    
    Metadata
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    Abstract
    Severe Acute Respiratory Syndrome (SARS) emerged in November 2002 as a case of atypical pneumonia in the Guandong Province in China. The causative agent SARS was identified as a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). Bone marrow stromal antigen 2 (or BST-2; also known as CD317 or tetherin) was initially identified as a pre-B-cell growth promoter but was identified as a viral antagonist. BST-2 inhibits the release of the retrovirus human immunodeficiency virus type 1 (HIV-1) virions by directly tethering budding virions from the host cell and further work has shown that BST-2 restricts the release of many other viruses, including alphaviruses, arenaviruses, herpesviruses, paramyxoviruses, and other retroviruses. BST-2 has recently been shown to restrict a human coronavirus, hCoV-229E. Many of these viruses, including hCoV-229E, are not only restricted by BST-2, but encode BST-2 antagonists to overcome BST-2 restriction. Given, the previous studies on BST-2, we aimed to determine if BST-2 has the ability to restrict SARS-CoV and if SARS-CoV encodes any BST-2 antagonists. Through an in vitro screen we identified four potential BST-2 antagonists, PL<sub>Pro</sub>, nsp1, ORF6, and ORF7a, encoded by SARS-CoV. Due to the gap in knowledge of the function of ORF7a, we focused our study on ORF7a. We found that BST-2 does restrict SARS-CoV, but the loss of ORF7a leads to a much greater restriction, which confirmed the role of ORF7a as a BST-2 antagonist. We further characterized the mechanism of BST-2 antagonism by ORF7a and found that ORF7a acts by a novel mechanism, localizes with and directly binds BST-2. ORF7a interferes with glycosylation of BST-2, although it is unclear whether ORF7a antagonizes BST-2 by blocking glycosylation or by binding to conserved patches of BST-2 and blocking glycosylation is just a side effect. We used a mouse model to evaluate the role of BST-2 in vivo and found that wild type and BST-2 -/- mice showed similar virus titer, weight loss, and lung pathology. While the BST-2 -/- mice did not show enhanced disease, there are several factors that may conceal a phenotype.
    Description
    University of Maryland, Baltimore. Molecular Microbiology and Immunology. Ph.D. 2014
    Keyword
    BST-2
    ORF7a
    SARS
    tetherin
    Coronavirus
    Severe Acute Respiratory Syndrome
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/4184
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    Theses and Dissertations School of Medicine
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