Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus
Identifieur interne : 000986 ( Pmc/Curation ); précédent : 000985; suivant : 000987Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus
Auteurs : Guangyu Zhao [République populaire de Chine] ; Yuting Jiang [République populaire de Chine] ; Hongjie Qiu [République populaire de Chine] ; Tongtong Gao [République populaire de Chine] ; Yang Zeng [République populaire de Chine] ; Yan Guo [République populaire de Chine] ; Hong Yu [République populaire de Chine] ; Junfeng Li [République populaire de Chine] ; Zhihua Kou [République populaire de Chine] ; Lanying Du [États-Unis] ; Wenjie Tan [République populaire de Chine] ; Shibo Jiang [États-Unis, République populaire de Chine] ; Shihui Sun [République populaire de Chine] ; Yusen Zhou [République populaire de Chine]Source :
- PLoS ONE [ 1932-6203 ] ; 2015.
Abstract
The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.
Url:
DOI: 10.1371/journal.pone.0145561
PubMed: 26701103
PubMed Central: 4689477
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<front><div type="abstract" xml:lang="en"><p>The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.</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, CA USA</publisher-loc>
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<article-meta><article-id pub-id-type="pmid">26701103</article-id>
<article-id pub-id-type="pmc">4689477</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0145561</article-id>
<article-id pub-id-type="publisher-id">PONE-D-15-32320</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
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<title-group><article-title>Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus</article-title>
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<given-names>Wenjie</given-names>
</name>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jiang</surname>
<given-names>Shibo</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sun</surname>
<given-names>Shihui</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref rid="cor001" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhou</surname>
<given-names>Yusen</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref rid="cor001" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, 10065, United States of America</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai, 200433, China</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Pöhlmann</surname>
<given-names>Stefan</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Deutsches Primatenzentrum GmbH - Leibniz-Institut fur Primatenforschung, GERMANY</addr-line>
</aff>
<author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: GZ SS Y. Zhou. Performed the experiments: GZ YJ HQ TG Y. Zeng YG HY SS. Analyzed the data: GZ SS JL ZK LD WT. Wrote the paper: GZ SS LD SJ Y. Zhou.</p>
</fn>
<corresp id="cor001">* E-mail: <email>yszhou@bmi.ac.cn</email>
(Y. Zhou); <email>sunsh01@163.com</email>
(SS)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>23</day>
<month>12</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><year>2015</year>
</pub-date>
<volume>10</volume>
<issue>12</issue>
<elocation-id>e0145561</elocation-id>
<history><date date-type="received"><day>31</day>
<month>7</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>4</day>
<month>12</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© 2015 Zhao et al</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>Zhao 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>
<self-uri content-type="pdf" xlink:type="simple" xlink:href="pone.0145561.pdf"></self-uri>
<abstract><p>The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.</p>
</abstract>
<funding-group><funding-statement>This work was supported by the National Project of Infectious Disease (2014ZX10004001004, 2012ZX10004502), the Basic Research 973 Project (2011CB504706), and the National Natural Science Foundation of China (81371805). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="5"></fig-count>
<table-count count="0"></table-count>
<page-count count="14"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the paper.</p>
</notes>
</front>
</pmc>
</record>
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