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Virus-Cell Interactions

Inhibition of Cytosolic Phospholipase A2α Impairs an Early Step of Coronavirus Replication in Cell Culture

Christin Müller, Martin Hardt, Dominik Schwudke, Benjamin W. Neuman, Stephan Pleschka, John Ziebuhr
Tom Gallagher, Editor
Christin Müller
aInstitute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
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Martin Hardt
bImaging Unit, Biomedical Research Center, Justus Liebig University Giessen, Giessen, Germany
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Dominik Schwudke
cDivision of Bioanalytical Chemistry, Priority Area Infection, Research Center Borstel, Leibniz Center for Medicine and Bioscience, Borstel, Germany
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Benjamin W. Neuman
dTexas A&M University, Texarkana, Texas, USA
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Stephan Pleschka
aInstitute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
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John Ziebuhr
aInstitute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
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Tom Gallagher
Loyola University Medical Center
Roles: Editor
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DOI: 10.1128/JVI.01463-17
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ABSTRACT

Coronavirus replication is associated with intracellular membrane rearrangements in infected cells, resulting in the formation of double-membrane vesicles (DMVs) and other membranous structures that are referred to as replicative organelles (ROs). The latter provide a structural scaffold for viral replication/transcription complexes (RTCs) and help to sequester RTC components from recognition by cellular factors involved in antiviral host responses. There is increasing evidence that plus-strand RNA (+RNA) virus replication, including RO formation and virion morphogenesis, affects cellular lipid metabolism and critically depends on enzymes involved in lipid synthesis and processing. Here, we investigated the role of cytosolic phospholipase A2α (cPLA2α) in coronavirus replication using a low-molecular-weight nonpeptidic inhibitor, pyrrolidine-2 (Py-2). The inhibition of cPLA2α activity, which produces lysophospholipids (LPLs) by cleaving at the sn-2 position of phospholipids, had profound effects on viral RNA and protein accumulation in human coronavirus 229E-infected Huh-7 cells. Transmission electron microscopy revealed that DMV formation in infected cells was significantly reduced in the presence of the inhibitor. Furthermore, we found that (i) viral RTCs colocalized with LPL-containing membranes, (ii) cellular LPL concentrations were increased in coronavirus-infected cells, and (iii) this increase was diminished in the presence of the cPLA2α inhibitor Py-2. Py-2 also displayed antiviral activities against other viruses representing the Coronaviridae and Togaviridae families, while members of the Picornaviridae were not affected. Taken together, the study provides evidence that cPLA2α activity is critically involved in the replication of various +RNA virus families and may thus represent a candidate target for broad-spectrum antiviral drug development.

IMPORTANCE Examples of highly conserved RNA virus proteins that qualify as drug targets for broad-spectrum antivirals remain scarce, resulting in increased efforts to identify and specifically inhibit cellular functions that are essential for the replication of RNA viruses belonging to different genera and families. The present study supports and extends previous conclusions that enzymes involved in cellular lipid metabolism may be tractable targets for broad-spectrum antivirals. We obtained evidence to show that a cellular phospholipase, cPLA2α, which releases fatty acid from the sn-2 position of membrane-associated glycerophospholipids, is critically involved in coronavirus replication, most likely by producing lysophospholipids that are required to form the specialized membrane compartments in which viral RNA synthesis takes place. The importance of this enzyme in coronavirus replication and DMV formation is supported by several lines of evidence, including confocal and electron microscopy, viral replication, and lipidomics studies of coronavirus-infected cells treated with a highly specific cPLA2α inhibitor.

FOOTNOTES

    • Received 25 August 2017.
    • Accepted 14 November 2017.
    • Accepted manuscript posted online 22 November 2017.
  • Supplemental material for this article may be found at https://doi.org/10.1128/JVI.01463-17.

  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

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Inhibition of Cytosolic Phospholipase A2α Impairs an Early Step of Coronavirus Replication in Cell Culture
Christin Müller, Martin Hardt, Dominik Schwudke, Benjamin W. Neuman, Stephan Pleschka, John Ziebuhr
Journal of Virology Jan 2018, 92 (4) e01463-17; DOI: 10.1128/JVI.01463-17

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Inhibition of Cytosolic Phospholipase A2α Impairs an Early Step of Coronavirus Replication in Cell Culture
Christin Müller, Martin Hardt, Dominik Schwudke, Benjamin W. Neuman, Stephan Pleschka, John Ziebuhr
Journal of Virology Jan 2018, 92 (4) e01463-17; DOI: 10.1128/JVI.01463-17
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