A mouse model for MERS coronavirus-induced acute respiratory distress syndrome
Identifieur interne : 000C67 ( Pmc/Checkpoint ); précédent : 000C66; suivant : 000C68A mouse model for MERS coronavirus-induced acute respiratory distress syndrome
Auteurs : Adam S. Cockrell ; Boyd L. Yount ; Trevor Scobey ; Kara Jensen ; Madeline Douglas ; Anne Beall ; Xian-Chun Tang [États-Unis] ; Wayne A. Marasco [États-Unis] ; Mark T. Heise ; Ralph S. BaricSource :
- Nature Microbiology [ 2058-5276 ] ; 2016.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV. Therefore, we used CRISPR–Cas9 gene editing to modify the mouse genome to encode two amino acids (positions 288 and 330) that match the human sequence in the dipeptidyl peptidase 4 receptor, making mice susceptible to MERS-CoV infection and replication. Serial MERS-CoV passage in these engineered mice was then used to generate a mouse-adapted virus that replicated efficiently within the lungs and evoked symptoms indicative of severe ARDS, including decreased survival, extreme weight loss, decreased pulmonary function, pulmonary haemorrhage and pathological signs indicative of end-stage lung disease. Importantly, therapeutic countermeasures comprising MERS-CoV neutralizing antibody treatment or a MERS-CoV spike protein vaccine protected the engineered mice against MERS-CoV-induced ARDS.
The online version of this article (doi:10.1038/nmicrobiol.2016.226) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1038/nmicrobiol.2016.226
PubMed: 27892925
PubMed Central: 5578707
Affiliations:
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<front><div type="abstract" xml:lang="en"><p id="Par1">Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV. Therefore, we used CRISPR–Cas9 gene editing to modify the mouse genome to encode two amino acids (positions 288 and 330) that match the human sequence in the dipeptidyl peptidase 4 receptor, making mice susceptible to MERS-CoV infection and replication. Serial MERS-CoV passage in these engineered mice was then used to generate a mouse-adapted virus that replicated efficiently within the lungs and evoked symptoms indicative of severe ARDS, including decreased survival, extreme weight loss, decreased pulmonary function, pulmonary haemorrhage and pathological signs indicative of end-stage lung disease. Importantly, therapeutic countermeasures comprising MERS-CoV neutralizing antibody treatment or a MERS-CoV spike protein vaccine protected the engineered mice against MERS-CoV-induced ARDS.</p>
<sec><title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/nmicrobiol.2016.226) contains supplementary material, which is available to authorized users.</p>
</sec>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Microbiol</journal-id>
<journal-id journal-id-type="iso-abbrev">Nat Microbiol</journal-id>
<journal-title-group><journal-title>Nature Microbiology</journal-title>
</journal-title-group>
<issn pub-type="epub">2058-5276</issn>
<publisher><publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27892925</article-id>
<article-id pub-id-type="pmc">5578707</article-id>
<article-id pub-id-type="publisher-id">BFnmicrobiol2016226</article-id>
<article-id pub-id-type="doi">10.1038/nmicrobiol.2016.226</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>A mouse model for MERS coronavirus-induced acute respiratory distress syndrome</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Cockrell</surname>
<given-names>Adam S.</given-names>
</name>
<address><email>adam_cockrell@unc.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yount</surname>
<given-names>Boyd L.</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Scobey</surname>
<given-names>Trevor</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jensen</surname>
<given-names>Kara</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Douglas</surname>
<given-names>Madeline</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Beall</surname>
<given-names>Anne</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tang</surname>
<given-names>Xian-Chun</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marasco</surname>
<given-names>Wayne A.</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Heise</surname>
<given-names>Mark T.</given-names>
</name>
<address><email>mark_heisem@med.unc.edu</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
<address><email>rbaric@email.unc.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="GRID">grid.10698.36</institution-id>
<institution-id institution-id-type="ISNI">0000000122483208</institution-id>
<institution>Department of Epidemiology,</institution>
<institution>University of North Carolina-Chapel Hill, Chapel Hill, North Carolina,</institution>
</institution-wrap>
27599 USA</aff>
<aff id="Aff2"><label>2</label>
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, 02215 USA</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="GRID">grid.38142.3c</institution-id>
<institution-id institution-id-type="ISNI">000000041936754X</institution-id>
<institution>Department of Medicine,</institution>
<institution>Harvard Medical School, Boston, Massachusetts,</institution>
</institution-wrap>
02115 USA</aff>
<aff id="Aff4"><label>4</label>
<institution-wrap><institution-id institution-id-type="GRID">grid.10698.36</institution-id>
<institution-id institution-id-type="ISNI">0000000122483208</institution-id>
<institution>Departments of Microbiology and Immunology,</institution>
<institution>University of North Carolina-Chapel Hill, Chapel Hill, North Carolina,</institution>
</institution-wrap>
27599 USA</aff>
<aff id="Aff5"><label>5</label>
<institution-wrap><institution-id institution-id-type="GRID">grid.10698.36</institution-id>
<institution-id institution-id-type="ISNI">0000000122483208</institution-id>
<institution>Departments of Genetics,</institution>
<institution>University of North Carolina-Chapel Hill, Chapel Hill, North Carolina,</institution>
</institution-wrap>
27599 USA</aff>
</contrib-group>
<pub-date pub-type="epub"><day>28</day>
<month>11</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><year>2017</year>
</pub-date>
<volume>2</volume>
<issue>2</issue>
<elocation-id>16226</elocation-id>
<history><date date-type="received"><day>27</day>
<month>4</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>14</day>
<month>10</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© Macmillan Publishers Limited 2016</copyright-statement>
<license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p id="Par1">Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV. Therefore, we used CRISPR–Cas9 gene editing to modify the mouse genome to encode two amino acids (positions 288 and 330) that match the human sequence in the dipeptidyl peptidase 4 receptor, making mice susceptible to MERS-CoV infection and replication. Serial MERS-CoV passage in these engineered mice was then used to generate a mouse-adapted virus that replicated efficiently within the lungs and evoked symptoms indicative of severe ARDS, including decreased survival, extreme weight loss, decreased pulmonary function, pulmonary haemorrhage and pathological signs indicative of end-stage lung disease. Importantly, therapeutic countermeasures comprising MERS-CoV neutralizing antibody treatment or a MERS-CoV spike protein vaccine protected the engineered mice against MERS-CoV-induced ARDS.</p>
<sec><title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/nmicrobiol.2016.226) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<abstract id="Abs2" abstract-type="web-summary"><p id="Par2">Mice made susceptible to MERS-CoV, using CRISPR–Cas9 to alter the gene encoding the dipeptidyl peptidase 4 receptor, allow efficient viral replication in the lungs and display symptoms indicative of severe acute respiratory stress.</p>
<sec><title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/nmicrobiol.2016.226) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group kwd-group-type="npg-subject"><title>Subject terms</title>
<kwd>Infection</kwd>
<kwd>Viral pathogenesis</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s), under exclusive licence to Springer Nature Limited 2017</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Massachusetts</li>
</region>
</list>
<tree><noCountry><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<name sortKey="Beall, Anne" sort="Beall, Anne" uniqKey="Beall A" first="Anne" last="Beall">Anne Beall</name>
<name sortKey="Cockrell, Adam S" sort="Cockrell, Adam S" uniqKey="Cockrell A" first="Adam S." last="Cockrell">Adam S. Cockrell</name>
<name sortKey="Douglas, Madeline" sort="Douglas, Madeline" uniqKey="Douglas M" first="Madeline" last="Douglas">Madeline Douglas</name>
<name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name>
<name sortKey="Jensen, Kara" sort="Jensen, Kara" uniqKey="Jensen K" first="Kara" last="Jensen">Kara Jensen</name>
<name sortKey="Scobey, Trevor" sort="Scobey, Trevor" uniqKey="Scobey T" first="Trevor" last="Scobey">Trevor Scobey</name>
<name sortKey="Yount, Boyd L" sort="Yount, Boyd L" uniqKey="Yount B" first="Boyd L." last="Yount">Boyd L. Yount</name>
</noCountry>
<country name="États-Unis"><region name="Massachusetts"><name sortKey="Tang, Xian Chun" sort="Tang, Xian Chun" uniqKey="Tang X" first="Xian-Chun" last="Tang">Xian-Chun Tang</name>
</region>
<name sortKey="Marasco, Wayne A" sort="Marasco, Wayne A" uniqKey="Marasco W" first="Wayne A." last="Marasco">Wayne A. Marasco</name>
</country>
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</affiliations>
</record>
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