Neurovirulent Murine Coronavirus JHM.SD Uses Cellular Zinc Metalloproteases for Virus Entry and Cell-Cell Fusion
Identifieur interne : 000605 ( Pmc/Checkpoint ); précédent : 000604; suivant : 000606Neurovirulent Murine Coronavirus JHM.SD Uses Cellular Zinc Metalloproteases for Virus Entry and Cell-Cell Fusion
Auteurs : Judith M. Phillips [États-Unis] ; Tom Gallagher [États-Unis] ; Susan R. Weiss [États-Unis]Source :
- Journal of Virology [ 0022-538X ] ; 2017.
Abstract
The coronavirus (CoV) S protein requires cleavage by host cell proteases to mediate virus-cell and cell-cell fusion. Many strains of the murine coronavirus mouse hepatitis virus (MHV) have distinct, S-dependent organ and tissue tropisms despite using a common receptor, suggesting that they employ different cellular proteases for fusion. In support of this hypothesis, we found that inhibition of endosomal acidification only modestly decreased entry, and overexpression of the cell surface protease TMPRSS2 greatly enhanced entry, of the highly neurovirulent MHV strain JHM.SD relative to their effects on the reference strain, A59. However, TMPRSS2 overexpression decreased MHV structural protein expression, release of infectious particles, and syncytium formation, and endogenous serine protease activity did not contribute greatly to infection. We therefore investigated the importance of other classes of cellular proteases and found that inhibition of matrix metalloproteinase (MMP)- and a disintegrin and metalloprotease (ADAM)-family zinc metalloproteases markedly decreased both entry and cell-cell fusion. Suppression of virus by metalloprotease inhibition varied among tested cell lines and MHV S proteins, suggesting a role for metalloprotease use in strain-dependent tropism. We conclude that zinc metalloproteases must be considered potential contributors to coronavirus fusion.
Url:
DOI: 10.1128/JVI.01564-16
PubMed: 28148786
PubMed Central: 5375694
Affiliations:
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>The coronavirus (CoV) S protein requires cleavage by host cell proteases to mediate virus-cell and cell-cell fusion. Many strains of the murine coronavirus mouse hepatitis virus (MHV) have distinct, S-dependent organ and tissue tropisms despite using a common receptor, suggesting that they employ different cellular proteases for fusion. In support of this hypothesis, we found that inhibition of endosomal acidification only modestly decreased entry, and overexpression of the cell surface protease TMPRSS2 greatly enhanced entry, of the highly neurovirulent MHV strain JHM.SD relative to their effects on the reference strain, A59. However, TMPRSS2 overexpression decreased MHV structural protein expression, release of infectious particles, and syncytium formation, and endogenous serine protease activity did not contribute greatly to infection. We therefore investigated the importance of other classes of cellular proteases and found that inhibition of matrix metalloproteinase (MMP)- and a disintegrin and metalloprotease (ADAM)-family zinc metalloproteases markedly decreased both entry and cell-cell fusion. Suppression of virus by metalloprotease inhibition varied among tested cell lines and MHV S proteins, suggesting a role for metalloprotease use in strain-dependent tropism. We conclude that zinc metalloproteases must be considered potential contributors to coronavirus fusion.</p>
<p><bold>IMPORTANCE</bold>
The family <named-content content-type="genus-species">Coronaviridae</named-content>
includes viruses that cause two emerging diseases of humans, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as a number of important animal pathogens. Because coronaviruses depend on host protease-mediated cleavage of their S proteins for entry, a number of protease inhibitors have been proposed as antiviral agents. However, it is unclear which proteases mediate <italic>in vivo</italic>
infection. For example, SARS-CoV infection of cultured cells depends on endosomal acid pH-dependent proteases rather than on the cell surface acid pH-independent serine protease TMPRSS2, but Zhou et al. (Antiviral Res 116:76–84, 2015, doi:10.1016/j.antiviral.2015.01.011) found that a serine protease inhibitor was more protective than a cathepsin inhibitor in SARS-CoV-infected mice. This paper explores the contributions of endosomal acidification and various proteases to coronavirus infection and identifies an unexpected class of proteases, the matrix metalloproteinase and ADAM families, as potential targets for anticoronavirus therapy.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Virol</journal-id>
<journal-id journal-id-type="hwp">jvi</journal-id>
<journal-id journal-id-type="pmc">jvi</journal-id>
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<journal-title-group><journal-title>Journal of Virology</journal-title>
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<issn pub-type="ppub">0022-538X</issn>
<issn pub-type="epub">1098-5514</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
<publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc>
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<article-id pub-id-type="publisher-id">01564-16</article-id>
<article-id pub-id-type="doi">10.1128/JVI.01564-16</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Virus-Cell Interactions</subject>
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</article-categories>
<title-group><article-title>Neurovirulent Murine Coronavirus JHM.SD Uses Cellular Zinc Metalloproteases for Virus Entry and Cell-Cell Fusion</article-title>
<alt-title alt-title-type="running-head">Metalloproteases in Murine Coronavirus Fusion</alt-title>
<alt-title alt-title-type="short-authors">Phillips et al.</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Phillips</surname>
<given-names>Judith M.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>a</sup>
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<contrib contrib-type="author"><name><surname>Gallagher</surname>
<given-names>Tom</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-8155-4528</contrib-id>
<name><surname>Weiss</surname>
<given-names>Susan R.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<aff id="aff1"><label>a</label>
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA</aff>
<aff id="aff2"><label>b</label>
Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, Illinois, USA</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Perlman</surname>
<given-names>Stanley</given-names>
</name>
<role>Editor</role>
<aff>University of Iowa</aff>
</contrib>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Judith M. Phillips, <email>jphil@upenn.edu</email>
.</corresp>
<fn fn-type="other"><p><bold>Citation</bold>
Phillips JM, Gallagher T, Weiss SR. 2017. Neurovirulent murine coronavirus JHM.SD uses cellular zinc metalloproteases for virus entry and cell-cell fusion. J Virol 91:e01564-16. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.01564-16">https://doi.org/10.1128/JVI.01564-16</ext-link>
.</p>
</fn>
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<pub-date pub-type="epreprint"><day>1</day>
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<year>2017</year>
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<pub-date pub-type="collection"><day>15</day>
<month>4</month>
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<volume>91</volume>
<issue>8</issue>
<elocation-id>e01564-16</elocation-id>
<history><date date-type="received"><day>5</day>
<month>8</month>
<year>2016</year>
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<date date-type="accepted"><day>24</day>
<month>1</month>
<year>2017</year>
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<permissions><copyright-statement>Copyright © 2017 American Society for Microbiology.</copyright-statement>
<copyright-year>2017</copyright-year>
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<abstract><title>ABSTRACT</title>
<p>The coronavirus (CoV) S protein requires cleavage by host cell proteases to mediate virus-cell and cell-cell fusion. Many strains of the murine coronavirus mouse hepatitis virus (MHV) have distinct, S-dependent organ and tissue tropisms despite using a common receptor, suggesting that they employ different cellular proteases for fusion. In support of this hypothesis, we found that inhibition of endosomal acidification only modestly decreased entry, and overexpression of the cell surface protease TMPRSS2 greatly enhanced entry, of the highly neurovirulent MHV strain JHM.SD relative to their effects on the reference strain, A59. However, TMPRSS2 overexpression decreased MHV structural protein expression, release of infectious particles, and syncytium formation, and endogenous serine protease activity did not contribute greatly to infection. We therefore investigated the importance of other classes of cellular proteases and found that inhibition of matrix metalloproteinase (MMP)- and a disintegrin and metalloprotease (ADAM)-family zinc metalloproteases markedly decreased both entry and cell-cell fusion. Suppression of virus by metalloprotease inhibition varied among tested cell lines and MHV S proteins, suggesting a role for metalloprotease use in strain-dependent tropism. We conclude that zinc metalloproteases must be considered potential contributors to coronavirus fusion.</p>
<p><bold>IMPORTANCE</bold>
The family <named-content content-type="genus-species">Coronaviridae</named-content>
includes viruses that cause two emerging diseases of humans, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as a number of important animal pathogens. Because coronaviruses depend on host protease-mediated cleavage of their S proteins for entry, a number of protease inhibitors have been proposed as antiviral agents. However, it is unclear which proteases mediate <italic>in vivo</italic>
infection. For example, SARS-CoV infection of cultured cells depends on endosomal acid pH-dependent proteases rather than on the cell surface acid pH-independent serine protease TMPRSS2, but Zhou et al. (Antiviral Res 116:76–84, 2015, doi:10.1016/j.antiviral.2015.01.011) found that a serine protease inhibitor was more protective than a cathepsin inhibitor in SARS-CoV-infected mice. This paper explores the contributions of endosomal acidification and various proteases to coronavirus infection and identifies an unexpected class of proteases, the matrix metalloproteinase and ADAM families, as potential targets for anticoronavirus therapy.</p>
</abstract>
<kwd-group><title>KEYWORDS</title>
<kwd>TMPRSS2</kwd>
<kwd>coronavirus</kwd>
<kwd>membrane fusion</kwd>
<kwd>metalloprotease</kwd>
<kwd>virus entry</kwd>
</kwd-group>
<funding-group><award-group id="award1"><funding-source id="gs1">HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
<named-content content-type="funder-id">https://doi.org/10.13039/100000060</named-content>
</funding-source>
<award-id rid="gs1">K08AI098503</award-id>
<principal-award-recipient>Judith Marie Phillips</principal-award-recipient>
</award-group>
<award-group id="award2"><funding-source id="gs2">HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
<named-content content-type="funder-id">https://doi.org/10.13039/100000060</named-content>
</funding-source>
<award-id rid="gs2">R01AI600210</award-id>
<principal-award-recipient>Susan R. Weiss</principal-award-recipient>
</award-group>
</funding-group>
<counts><fig-count count="9"></fig-count>
<table-count count="1"></table-count>
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<custom-meta-group><custom-meta><meta-name>cover-date</meta-name>
<meta-value>April 2017</meta-value>
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<affiliations><list><country><li>États-Unis</li>
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