Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4
Identifieur interne : 000038 ( Pmc/Corpus ); précédent : 000037; suivant : 000039Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4
Auteurs : Kun Li ; Christine Wohlford-Lenane ; Stanley Perlman ; Jincun Zhao ; Alexander K. Jewell ; Leah R. Reznikov ; Katherine N. Gibson-Corley ; David K. Meyerholz ; Paul B. MccraySource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2015.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) causes life-threatening disease. Dipeptidyl peptidase 4 (DPP4) is the receptor for cell binding and entry. There is a need for small-animal models of MERS, but mice are not susceptible to MERS because murine dpp4 does not serve as a receptor. We developed transgenic mice expressing human DPP4 (hDPP4) under the control of the surfactant protein C promoter or cytokeratin 18 promoter that are susceptible to infection with MERS-CoV. Notably, mice expressing hDPP4 with the cytokeratin 18 promoter developed progressive, uniformly fatal disease following intranasal inoculation. High virus titers were present in lung and brain tissues 2 and 6 days after infection, respectively. MERS-CoV–infected lungs revealed mononuclear cell infiltration, alveolar edema, and microvascular thrombosis, with airways generally unaffected. Brain disease was observed, with the greatest involvement noted in the thalamus and brain stem. Animals immunized with a vaccine candidate were uniformly protected from lethal infection. These new mouse models of MERS-CoV should be useful for investigation of early disease mechanisms and therapeutic interventions.
Url:
DOI: 10.1093/infdis/jiv499
PubMed: 26486634
PubMed Central: 4747621
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4</title><author><name sortKey="Li, Kun" sort="Li, Kun" uniqKey="Li K" first="Kun" last="Li">Kun Li</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wohlford Lenane, Christine" sort="Wohlford Lenane, Christine" uniqKey="Wohlford Lenane C" first="Christine" last="Wohlford-Lenane">Christine Wohlford-Lenane</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><addr-line>Department of Microbiology</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af5"><addr-line>Interdisciplinary Program in Immunology</addr-line>,<institution>University of Iowa</institution>,<addr-line>Iowa City</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Jincun" sort="Zhao, Jincun" uniqKey="Zhao J" first="Jincun" last="Zhao">Jincun Zhao</name><affiliation><nlm:aff id="af2"><addr-line>Department of Microbiology</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jewell, Alexander K" sort="Jewell, Alexander K" uniqKey="Jewell A" first="Alexander K." last="Jewell">Alexander K. Jewell</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reznikov, Leah R" sort="Reznikov, Leah R" uniqKey="Reznikov L" first="Leah R." last="Reznikov">Leah R. Reznikov</name><affiliation><nlm:aff id="af3"><addr-line>Department of Internal Medicine</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gibson Corley, Katherine N" sort="Gibson Corley, Katherine N" uniqKey="Gibson Corley K" first="Katherine N." last="Gibson-Corley">Katherine N. Gibson-Corley</name><affiliation><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K." last="Meyerholz">David K. Meyerholz</name><affiliation><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B." last="Mccray">Paul B. Mccray</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><addr-line>Department of Microbiology</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26486634</idno><idno type="pmc">4747621</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747621</idno><idno type="RBID">PMC:4747621</idno><idno type="doi">10.1093/infdis/jiv499</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000038</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000038</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4</title><author><name sortKey="Li, Kun" sort="Li, Kun" uniqKey="Li K" first="Kun" last="Li">Kun Li</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wohlford Lenane, Christine" sort="Wohlford Lenane, Christine" uniqKey="Wohlford Lenane C" first="Christine" last="Wohlford-Lenane">Christine Wohlford-Lenane</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><addr-line>Department of Microbiology</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af5"><addr-line>Interdisciplinary Program in Immunology</addr-line>,<institution>University of Iowa</institution>,<addr-line>Iowa City</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Jincun" sort="Zhao, Jincun" uniqKey="Zhao J" first="Jincun" last="Zhao">Jincun Zhao</name><affiliation><nlm:aff id="af2"><addr-line>Department of Microbiology</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jewell, Alexander K" sort="Jewell, Alexander K" uniqKey="Jewell A" first="Alexander K." last="Jewell">Alexander K. Jewell</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reznikov, Leah R" sort="Reznikov, Leah R" uniqKey="Reznikov L" first="Leah R." last="Reznikov">Leah R. Reznikov</name><affiliation><nlm:aff id="af3"><addr-line>Department of Internal Medicine</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gibson Corley, Katherine N" sort="Gibson Corley, Katherine N" uniqKey="Gibson Corley K" first="Katherine N." last="Gibson-Corley">Katherine N. Gibson-Corley</name><affiliation><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K." last="Meyerholz">David K. Meyerholz</name><affiliation><nlm:aff id="af4"><addr-line>Department of Pathology</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B." last="Mccray">Paul B. Mccray</name><affiliation><nlm:aff id="af1"><addr-line>Department of Pediatrics</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><addr-line>Department of Microbiology</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Middle East respiratory syndrome coronavirus (MERS-CoV) causes life-threatening disease. Dipeptidyl peptidase 4 (DPP4) is the receptor for cell binding and entry. There is a need for small-animal models of MERS, but mice are not susceptible to MERS because murine dpp4 does not serve as a receptor. We developed transgenic mice expressing human DPP4 (hDPP4) under the control of the surfactant protein C promoter or cytokeratin 18 promoter that are susceptible to infection with MERS-CoV. Notably, mice expressing hDPP4 with the cytokeratin 18 promoter developed progressive, uniformly fatal disease following intranasal inoculation. High virus titers were present in lung and brain tissues 2 and 6 days after infection, respectively. MERS-CoV–infected lungs revealed mononuclear cell infiltration, alveolar edema, and microvascular thrombosis, with airways generally unaffected. Brain disease was observed, with the greatest involvement noted in the thalamus and brain stem. Animals immunized with a vaccine candidate were uniformly protected from lethal infection. These new mouse models of MERS-CoV should be useful for investigation of early disease mechanisms and therapeutic interventions.</p></div></front></TEI><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 Infect Dis</journal-id><journal-id journal-id-type="iso-abbrev">J. Infect. Dis</journal-id><journal-id journal-id-type="publisher-id">jid</journal-id><journal-id journal-id-type="hwp">jinfdis</journal-id><journal-title-group><journal-title>The Journal of Infectious Diseases</journal-title></journal-title-group><issn pub-type="ppub">0022-1899</issn><issn pub-type="epub">1537-6613</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26486634</article-id><article-id pub-id-type="pmc">4747621</article-id><article-id pub-id-type="doi">10.1093/infdis/jiv499</article-id><article-id pub-id-type="publisher-id">jiv499</article-id><article-categories><subj-group subj-group-type="heading"><subject>Major Articles and Brief Reports</subject><subj-group subj-group-type="heading"><subject>Viruses</subject></subj-group></subj-group></article-categories><title-group><article-title>Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Li</surname><given-names>Kun</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wohlford-Lenane</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Perlman</surname><given-names>Stanley</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Jincun</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Jewell</surname><given-names>Alexander K.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Reznikov</surname><given-names>Leah R.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Gibson-Corley</surname><given-names>Katherine N.</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Meyerholz</surname><given-names>David K.</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>McCray</surname><given-names>Paul B.</given-names><suffix>Jr</suffix></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><aff id="af1"><label>1</label><addr-line>Department of Pediatrics</addr-line></aff><aff id="af2"><label>2</label><addr-line>Department of Microbiology</addr-line></aff><aff id="af3"><label>3</label><addr-line>Department of Internal Medicine</addr-line></aff><aff id="af4"><label>4</label><addr-line>Department of Pathology</addr-line></aff><aff id="af5"><label>5</label><addr-line>Interdisciplinary Program in Immunology</addr-line>,<institution>University of Iowa</institution>,<addr-line>Iowa City</addr-line></aff></contrib-group><author-notes><corresp>Correspondence: P. B. McCray, Department of Pediatrics, 6320 PBDB, University of Iowa, Iowa City, IA 52242 (<email>paul-mccray@uiowa.edu</email>).</corresp></author-notes><pub-date pub-type="ppub"><day>01</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>20</day><month>10</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>3</month><year>2017</year></pub-date><pmc-comment> PMC Release delay is 12 months and
0 days and was based on the
<volume>213</volume><issue>5</issue><fpage>712</fpage><lpage>722</lpage><history><date date-type="received"><day>25</day><month>6</month><year>2015</year></date><date date-type="accepted"><day>8</day><month>10</month><year>2015</year></date></history><permissions><copyright-statement>© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail <email>journals.permissions@oup.com</email>.</copyright-statement><copyright-year>2015</copyright-year></permissions><self-uri content-type="pdf" xlink:href="jiv499.pdf"></self-uri><abstract><p>Middle East respiratory syndrome coronavirus (MERS-CoV) causes life-threatening disease. Dipeptidyl peptidase 4 (DPP4) is the receptor for cell binding and entry. There is a need for small-animal models of MERS, but mice are not susceptible to MERS because murine dpp4 does not serve as a receptor. We developed transgenic mice expressing human DPP4 (hDPP4) under the control of the surfactant protein C promoter or cytokeratin 18 promoter that are susceptible to infection with MERS-CoV. Notably, mice expressing hDPP4 with the cytokeratin 18 promoter developed progressive, uniformly fatal disease following intranasal inoculation. High virus titers were present in lung and brain tissues 2 and 6 days after infection, respectively. MERS-CoV–infected lungs revealed mononuclear cell infiltration, alveolar edema, and microvascular thrombosis, with airways generally unaffected. Brain disease was observed, with the greatest involvement noted in the thalamus and brain stem. Animals immunized with a vaccine candidate were uniformly protected from lethal infection. These new mouse models of MERS-CoV should be useful for investigation of early disease mechanisms and therapeutic interventions.</p></abstract><kwd-group><kwd>transgenic mice</kwd><kwd>MERS</kwd><kwd>DPP4/CD26</kwd></kwd-group><funding-group><award-group id="funding-1"><funding-source>National Institutes of Health <named-content content-type="funder-id">http://dx.doi.org/10.13039/100000002</named-content></funding-source></award-group><award-group id="funding-2"><funding-source>NIH</funding-source><award-id>PO1 AI060699</award-id></award-group><award-group id="funding-3"><funding-source>Cell Morphology Core and Pathology Core</funding-source></award-group><award-group id="funding-4"><funding-source>Center for Gene Therapy for Cystic Fibrosis</funding-source></award-group><award-group id="funding-5"><funding-source>NIH</funding-source><award-id>P30 DK-54759</award-id></award-group><award-group id="funding-6"><funding-source>Cystic Fibrosis Foundation <named-content content-type="funder-id">http://dx.doi.org/10.13039/100000897</named-content></funding-source></award-group><award-group id="funding-7"><funding-source>College of Medicine</funding-source></award-group><award-group id="funding-8"><funding-source>Center for Gene Therapy for Cystic Fibrosis</funding-source></award-group><award-group id="funding-9"><funding-source>Roy J. Carver Charitable Trust <named-content content-type="funder-id">http://dx.doi.org/10.13039/100001024</named-content></funding-source></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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