Role of the Spike Glycoprotein of Human Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Virus Entry and Syncytia Formation
Identifieur interne : 001182 ( Pmc/Checkpoint ); précédent : 001181; suivant : 001183Role of the Spike Glycoprotein of Human Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Virus Entry and Syncytia Formation
Auteurs : Zhaohui Qian [États-Unis, République populaire de Chine] ; Samuel R. Dominguez [États-Unis] ; Kathryn V. Holmes [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
Little is known about the biology of the emerging human group c betacoronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV). Because coronavirus spike glycoproteins (S) mediate virus entry, affect viral host range, and elicit neutralizing antibodies, analyzing the functions of MERS-CoV S protein is a high research priority. MERS-CoV S on lentivirus pseudovirions mediated entry into a variety of cell types including embryo cells from New World
Url:
DOI: 10.1371/journal.pone.0076469
PubMed: 24098509
PubMed Central: 3789674
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>Little is known about the biology of the emerging human group c betacoronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV). Because coronavirus spike glycoproteins (S) mediate virus entry, affect viral host range, and elicit neutralizing antibodies, analyzing the functions of MERS-CoV S protein is a high research priority. MERS-CoV S on lentivirus pseudovirions mediated entry into a variety of cell types including embryo cells from New World <italic>Eptesicus fuscus</italic>
bats. Surprisingly, a polyclonal antibody to the S protein of MHV, a group a murine betacoronavirus, cross-reacted in immunoblots with the S2 domain of group c MERS-CoV spike protein. MERS pseudovirions released from 293T cells contained only uncleaved S, and pseudovirus entry was blocked by lysosomotropic reagents NH<sub>4</sub>
Cl and bafilomycin and inhibitors of cathepsin L. However, when MERS pseudovirions with uncleaved S protein were adsorbed at 4°C to Vero E6 cells, brief trypsin treatment at neutral pH triggered virus entry at the plasma membrane and syncytia formation. When 293T cells producing MERS pseudotypes co-expressed serine proteases TMPRSS-2 or -4, large syncytia formed at neutral pH, and the pseudovirions produced were non-infectious and deficient in S protein. These experiments show that if S protein on MERS pseudovirions is uncleaved, then viruses enter by endocytosis in a cathepsin L-dependent manner, but if MERS-CoV S is cleaved, either during virus maturation by serine proteases or on pseudovirions by trypsin in extracellular fluids, then viruses enter at the plasma membrane at neutral pH and cause massive syncytia formation even in cells that express little or no MERS-CoV receptor. Thus, whether MERS-CoV enters cells within endosomes or at the plasma membrane depends upon the host cell type and tissue, and is determined by the location of host proteases that cleave the viral spike glycoprotein and activate membrane fusion.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group><journal-title>PLoS ONE</journal-title>
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<issn pub-type="epub">1932-6203</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">24098509</article-id>
<article-id pub-id-type="pmc">3789674</article-id>
<article-id pub-id-type="publisher-id">PONE-D-13-26136</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0076469</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Role of the Spike Glycoprotein of Human Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Virus Entry and Syncytia Formation</article-title>
<alt-title alt-title-type="running-head">MERS-CoV Spike Protein in Virus Entry</alt-title>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dominguez</surname>
<given-names>Samuel R.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Holmes</surname>
<given-names>Kathryn V.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Ren</surname>
<given-names>Xiaofeng</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Northeast Agricultural University, China</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>kathryn.holmes@ucdenver.edu</email>
</corresp>
<fn fn-type="COI-statement"><p><bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: ZQ SRD KVH. Performed the experiments: ZQ. Analyzed the data: ZQ SRD KVH. Contributed reagents/materials/analysis tools: ZQ SRD KVH. Wrote the manuscript: ZQ SRD KVH. </p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>3</day>
<month>10</month>
<year>2013</year>
</pub-date>
<volume>8</volume>
<issue>10</issue>
<elocation-id>e76469</elocation-id>
<history><date date-type="received"><day>24</day>
<month>6</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>29</day>
<month>8</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>© 2013 Qian et al</copyright-statement>
<copyright-year>2013</copyright-year>
<copyright-holder>Qian et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>Little is known about the biology of the emerging human group c betacoronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV). Because coronavirus spike glycoproteins (S) mediate virus entry, affect viral host range, and elicit neutralizing antibodies, analyzing the functions of MERS-CoV S protein is a high research priority. MERS-CoV S on lentivirus pseudovirions mediated entry into a variety of cell types including embryo cells from New World <italic>Eptesicus fuscus</italic>
bats. Surprisingly, a polyclonal antibody to the S protein of MHV, a group a murine betacoronavirus, cross-reacted in immunoblots with the S2 domain of group c MERS-CoV spike protein. MERS pseudovirions released from 293T cells contained only uncleaved S, and pseudovirus entry was blocked by lysosomotropic reagents NH<sub>4</sub>
Cl and bafilomycin and inhibitors of cathepsin L. However, when MERS pseudovirions with uncleaved S protein were adsorbed at 4°C to Vero E6 cells, brief trypsin treatment at neutral pH triggered virus entry at the plasma membrane and syncytia formation. When 293T cells producing MERS pseudotypes co-expressed serine proteases TMPRSS-2 or -4, large syncytia formed at neutral pH, and the pseudovirions produced were non-infectious and deficient in S protein. These experiments show that if S protein on MERS pseudovirions is uncleaved, then viruses enter by endocytosis in a cathepsin L-dependent manner, but if MERS-CoV S is cleaved, either during virus maturation by serine proteases or on pseudovirions by trypsin in extracellular fluids, then viruses enter at the plasma membrane at neutral pH and cause massive syncytia formation even in cells that express little or no MERS-CoV receptor. Thus, whether MERS-CoV enters cells within endosomes or at the plasma membrane depends upon the host cell type and tissue, and is determined by the location of host proteases that cleave the viral spike glycoprotein and activate membrane fusion.</p>
</abstract>
<funding-group><funding-statement>This work was supported in part by the State of Colorado Bioscience Discovery Evaluation Grant Program (HB-07-1001) and NIH grant K08 AI-073525 to SRD. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.</funding-statement>
</funding-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Colorado</li>
</region>
<settlement><li>Pékin</li>
</settlement>
</list>
<tree><country name="États-Unis"><region name="Colorado"><name sortKey="Qian, Zhaohui" sort="Qian, Zhaohui" uniqKey="Qian Z" first="Zhaohui" last="Qian">Zhaohui Qian</name>
</region>
<name sortKey="Dominguez, Samuel R" sort="Dominguez, Samuel R" uniqKey="Dominguez S" first="Samuel R." last="Dominguez">Samuel R. Dominguez</name>
<name sortKey="Dominguez, Samuel R" sort="Dominguez, Samuel R" uniqKey="Dominguez S" first="Samuel R." last="Dominguez">Samuel R. Dominguez</name>
<name sortKey="Holmes, Kathryn V" sort="Holmes, Kathryn V" uniqKey="Holmes K" first="Kathryn V." last="Holmes">Kathryn V. Holmes</name>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Qian, Zhaohui" sort="Qian, Zhaohui" uniqKey="Qian Z" first="Zhaohui" last="Qian">Zhaohui Qian</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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