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    Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors

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    Author
    Sisk, J.M.
    Frieman, M.B.
    Machamer, C.E.
    Date
    2018
    Journal
    Journal of General Virology
    Publisher
    Microbiology Society
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1099/jgv.0.001047
    Abstract
    Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARSCoV and MERS-CoV are classified as BSL-3 viruses, which makes experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titres by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying the host cell pathways required for coronavirus infection. This will provide an insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses. Copyright 2018 The Authors.
    Sponsors
    This was supported by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI118303 (J. M. S) and R01AI095569 (M. B. F).
    Keyword
    Abl kinase
    Abl1
    Abl2
    Cell-cell fusion
    Coronavirus
    GNF2
    GNF5
    IBV
    Imatinib
    MERS-CoV
    SARS-CoV
    Virus-cell fusion
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    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85046402518&doi=10.1099%2fjgv.0.001047&partnerID=40&md5=8095ccd01c2d850e9969af28c7edbe0a; http://hdl.handle.net/10713/12394
    ae974a485f413a2113503eed53cd6c53
    10.1099/jgv.0.001047
    Scopus Count
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    UMB Coronavirus Publications

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