Severe Acute Respiratory Syndrome Coronaviruses with Mutations in the E Protein Are Attenuated and Promising Vaccine Candidates
Identifieur interne : 000766 ( Pmc/Checkpoint ); précédent : 000765; suivant : 000767Severe Acute Respiratory Syndrome Coronaviruses with Mutations in the E Protein Are Attenuated and Promising Vaccine Candidates
Auteurs : Jose A. Regla-Nava [Espagne] ; Jose L. Nieto-Torres [Espagne] ; Jose M. Jimenez-Guarde O [Espagne] ; Raul Fernandez-Delgado [Espagne] ; Craig Fett [États-Unis] ; Carlos Casta O-Rodríguez [Espagne] ; Stanley Perlman [États-Unis] ; Luis Enjuanes [Espagne] ; Marta L. Dediego [Espagne]Source :
- Journal of Virology [ 0022-538X ] ; 2015.
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) causes a respiratory disease with a mortality rate of 10%. A mouse-adapted SARS-CoV (SARS-CoV-MA15) lacking the envelope (E) protein (rSARS-CoV-MA15-ΔE) is attenuated
Url:
DOI: 10.1128/JVI.03566-14
PubMed: 25609816
PubMed Central: 4403406
Affiliations:
- Espagne, États-Unis
- Communauté de Madrid, Iowa
- Iowa City, Madrid
- Université autonome de Madrid, Université de l'Iowa
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<author><name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raul" last="Fernandez-Delgado">Raul Fernandez-Delgado</name>
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<author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name>
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<author><name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L." last="Dediego">Marta L. Dediego</name>
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Severe acute respiratory syndrome coronavirus (SARS-CoV) causes a respiratory disease with a mortality rate of 10%. A mouse-adapted SARS-CoV (SARS-CoV-MA15) lacking the envelope (E) protein (rSARS-CoV-MA15-ΔE) is attenuated <italic>in vivo</italic>
. To identify E protein regions and host responses that contribute to rSARS-CoV-MA15-ΔE attenuation, several mutants (rSARS-CoV-MA15-E*) containing point mutations or deletions in the amino-terminal or the carboxy-terminal regions of the E protein were generated. Amino acid substitutions in the amino terminus, or deletion of regions in the internal carboxy-terminal region of E protein, led to virus attenuation. Attenuated viruses induced minimal lung injury, diminished limited neutrophil influx, and increased CD4<sup>+</sup>
and CD8<sup>+</sup>
T cell counts in the lungs of BALB/c mice, compared to mice infected with the wild-type virus. To analyze the host responses leading to rSARS-CoV-MA15-E* attenuation, differences in gene expression elicited by the native and mutant viruses in the lungs of infected mice were determined. Expression levels of a large number of proinflammatory cytokines associated with lung injury were reduced in the lungs of rSARS-CoV-MA15-E*-infected mice, whereas the levels of anti-inflammatory cytokines were increased, both at the mRNA and protein levels. These results suggested that the reduction in lung inflammation together with a more robust antiviral T cell response contributed to rSARS-CoV-MA15-E* attenuation. The attenuated viruses completely protected mice against challenge with the lethal parental virus, indicating that these viruses are promising vaccine candidates.</p>
<p><bold>IMPORTANCE</bold>
Human coronaviruses are important zoonotic pathogens. SARS-CoV caused a worldwide epidemic infecting more than 8,000 people with a mortality of around 10%. Therefore, understanding the virulence mechanisms of this pathogen and developing efficacious vaccines are of high importance to prevent epidemics from this and other human coronaviruses. Previously, we demonstrated that a SARS-CoV lacking the E protein was attenuated <italic>in vivo</italic>
. Here, we show that small deletions and modifications within the E protein led to virus attenuation, manifested by minimal lung injury, limited neutrophil influx to the lungs, reduced expression of proinflammatory cytokines, increased anti-inflammatory cytokine levels, and enhanced CD4<sup>+</sup>
and CD8<sup>+</sup>
T cell counts <italic>in vivo</italic>
, suggesting that these phenomena contribute to virus attenuation. The attenuated mutants fully protected mice from challenge with virulent virus. These studies show that mutations in the E protein are not well tolerated and indicate that this protein is an excellent target for vaccine development.</p>
</div>
</front>
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<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>
<journal-id journal-id-type="publisher-id">JVI</journal-id>
<journal-title-group><journal-title>Journal of Virology</journal-title>
</journal-title-group>
<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>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25609816</article-id>
<article-id pub-id-type="pmc">4403406</article-id>
<article-id pub-id-type="publisher-id">03566-14</article-id>
<article-id pub-id-type="doi">10.1128/JVI.03566-14</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Vaccines and Antiviral Agents</subject>
</subj-group>
</article-categories>
<title-group><article-title>Severe Acute Respiratory Syndrome Coronaviruses with Mutations in the E Protein Are Attenuated and Promising Vaccine Candidates</article-title>
<alt-title alt-title-type="running-head">SARS-CoV E Protein Mutants and Virus Attenuation</alt-title>
<alt-title alt-title-type="short-authors">Regla-Nava et al.</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Regla-Nava</surname>
<given-names>Jose A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nieto-Torres</surname>
<given-names>Jose L.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jimenez-Guardeño</surname>
<given-names>Jose M.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fernandez-Delgado</surname>
<given-names>Raul</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fett</surname>
<given-names>Craig</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Castaño-Rodríguez</surname>
<given-names>Carlos</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Perlman</surname>
<given-names>Stanley</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Enjuanes</surname>
<given-names>Luis</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>DeDiego</surname>
<given-names>Marta L.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<aff id="aff1"><label>a</label>
Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Campus Universidad Autónoma de Madrid, Madrid, Spain</aff>
<aff id="aff2"><label>b</label>
Department of Microbiology, University of Iowa, Iowa City, Iowa, USA</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Dermody</surname>
<given-names>T. S.</given-names>
</name>
<role>Editor</role>
</contrib>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Luis Enjuanes, <email>L.Enjuanes@cnb.csic.es</email>
.</corresp>
<fn id="fn1" fn-type="present-address"><label>*</label>
<p>Present address: Marta L. DeDiego, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.</p>
</fn>
<fn fn-type="other"><p><bold>Citation</bold>
Regla-Nava JA, Nieto-Torres JL, Jimenez-Guardeño JM, Fernandez-Delgado R, Fett C, Castaño-Rodríguez C, Perlman S, Enjuanes L, DeDiego ML. 2015. Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates. J Virol 89:3870–3887. doi:<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1128/JVI.03566-14">10.1128/JVI.03566-14</ext-link>
.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>21</day>
<month>1</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><day>1</day>
<month>4</month>
<year>2015</year>
</pub-date>
<volume>89</volume>
<issue>7</issue>
<fpage>3870</fpage>
<lpage>3887</lpage>
<history><date date-type="received"><day>12</day>
<month>12</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>14</day>
<month>1</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>American Society for Microbiology</copyright-holder>
</permissions>
<self-uri content-type="pdf" xlink:href="zjv00715003870.pdf"></self-uri>
<abstract><title>ABSTRACT</title>
<p>Severe acute respiratory syndrome coronavirus (SARS-CoV) causes a respiratory disease with a mortality rate of 10%. A mouse-adapted SARS-CoV (SARS-CoV-MA15) lacking the envelope (E) protein (rSARS-CoV-MA15-ΔE) is attenuated <italic>in vivo</italic>
. To identify E protein regions and host responses that contribute to rSARS-CoV-MA15-ΔE attenuation, several mutants (rSARS-CoV-MA15-E*) containing point mutations or deletions in the amino-terminal or the carboxy-terminal regions of the E protein were generated. Amino acid substitutions in the amino terminus, or deletion of regions in the internal carboxy-terminal region of E protein, led to virus attenuation. Attenuated viruses induced minimal lung injury, diminished limited neutrophil influx, and increased CD4<sup>+</sup>
and CD8<sup>+</sup>
T cell counts in the lungs of BALB/c mice, compared to mice infected with the wild-type virus. To analyze the host responses leading to rSARS-CoV-MA15-E* attenuation, differences in gene expression elicited by the native and mutant viruses in the lungs of infected mice were determined. Expression levels of a large number of proinflammatory cytokines associated with lung injury were reduced in the lungs of rSARS-CoV-MA15-E*-infected mice, whereas the levels of anti-inflammatory cytokines were increased, both at the mRNA and protein levels. These results suggested that the reduction in lung inflammation together with a more robust antiviral T cell response contributed to rSARS-CoV-MA15-E* attenuation. The attenuated viruses completely protected mice against challenge with the lethal parental virus, indicating that these viruses are promising vaccine candidates.</p>
<p><bold>IMPORTANCE</bold>
Human coronaviruses are important zoonotic pathogens. SARS-CoV caused a worldwide epidemic infecting more than 8,000 people with a mortality of around 10%. Therefore, understanding the virulence mechanisms of this pathogen and developing efficacious vaccines are of high importance to prevent epidemics from this and other human coronaviruses. Previously, we demonstrated that a SARS-CoV lacking the E protein was attenuated <italic>in vivo</italic>
. Here, we show that small deletions and modifications within the E protein led to virus attenuation, manifested by minimal lung injury, limited neutrophil influx to the lungs, reduced expression of proinflammatory cytokines, increased anti-inflammatory cytokine levels, and enhanced CD4<sup>+</sup>
and CD8<sup>+</sup>
T cell counts <italic>in vivo</italic>
, suggesting that these phenomena contribute to virus attenuation. The attenuated mutants fully protected mice from challenge with virulent virus. These studies show that mutations in the E protein are not well tolerated and indicate that this protein is an excellent target for vaccine development.</p>
</abstract>
<counts><fig-count count="14"></fig-count>
<table-count count="3"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="89"></ref-count>
<page-count count="18"></page-count>
<word-count count="12284"></word-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Espagne</li>
<li>États-Unis</li>
</country>
<region><li>Communauté de Madrid</li>
<li>Iowa</li>
</region>
<settlement><li>Iowa City</li>
<li>Madrid</li>
</settlement>
<orgName><li>Université autonome de Madrid</li>
<li>Université de l'Iowa</li>
</orgName>
</list>
<tree><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Regla Nava, Jose A" sort="Regla Nava, Jose A" uniqKey="Regla Nava J" first="Jose A." last="Regla-Nava">Jose A. Regla-Nava</name>
</region>
<name sortKey="Casta O Rodriguez, Carlos" sort="Casta O Rodriguez, Carlos" uniqKey="Casta O Rodriguez C" first="Carlos" last="Casta O-Rodríguez">Carlos Casta O-Rodríguez</name>
<name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L." last="Dediego">Marta L. Dediego</name>
<name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name>
<name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raul" last="Fernandez-Delgado">Raul Fernandez-Delgado</name>
<name sortKey="Jimenez Guarde O, Jose M" sort="Jimenez Guarde O, Jose M" uniqKey="Jimenez Guarde O J" first="Jose M." last="Jimenez-Guarde O">Jose M. Jimenez-Guarde O</name>
<name sortKey="Nieto Torres, Jose L" sort="Nieto Torres, Jose L" uniqKey="Nieto Torres J" first="Jose L." last="Nieto-Torres">Jose L. Nieto-Torres</name>
</country>
<country name="États-Unis"><region name="Iowa"><name sortKey="Fett, Craig" sort="Fett, Craig" uniqKey="Fett C" first="Craig" last="Fett">Craig Fett</name>
</region>
<name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name>
</country>
</tree>
</affiliations>
</record>
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