Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus
Identifieur interne : 001063 ( Main/Exploration ); précédent : 001062; suivant : 001064Multi-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
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus</title><author><name sortKey="Zhao, Guangyu" sort="Zhao, Guangyu" uniqKey="Zhao G" first="Guangyu" last="Zhao">Guangyu Zhao</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Jiang, Yuting" sort="Jiang, Yuting" uniqKey="Jiang Y" first="Yuting" last="Jiang">Yuting Jiang</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State 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China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Guo, Yan" sort="Guo, Yan" uniqKey="Guo Y" first="Yan" last="Guo">Yan Guo</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Yu, Hong" sort="Yu, Hong" uniqKey="Yu H" first="Hong" last="Yu">Hong 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Jiang</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Qiu, Hongjie" sort="Qiu, Hongjie" uniqKey="Qiu H" first="Hongjie" last="Qiu">Hongjie Qiu</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Gao, Tongtong" sort="Gao, Tongtong" uniqKey="Gao T" first="Tongtong" last="Gao">Tongtong Gao</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Zeng, Yang" sort="Zeng, Yang" uniqKey="Zeng Y" first="Yang" last="Zeng">Yang Zeng</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Guo, Yan" sort="Guo, Yan" uniqKey="Guo Y" first="Yan" last="Guo">Yan Guo</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Yu, Hong" sort="Yu, Hong" uniqKey="Yu H" first="Hong" last="Yu">Hong Yu</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Li, Junfeng" sort="Li, Junfeng" uniqKey="Li J" first="Junfeng" last="Li">Junfeng Li</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Kou, Zhihua" sort="Kou, Zhihua" uniqKey="Kou Z" first="Zhihua" last="Kou">Zhihua Kou</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, 10065, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, 10065</wicri:regionArea><wicri:noRegion>10065</wicri:noRegion></affiliation></author><author><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><affiliation wicri:level="1"><nlm:aff id="aff004"><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></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206</wicri:regionArea><wicri:noRegion>102206</wicri:noRegion></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, 10065, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, 10065</wicri:regionArea><wicri:noRegion>10065</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai, 200433, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai, 200433</wicri:regionArea><wicri:noRegion>200433</wicri:noRegion></affiliation></author><author><name sortKey="Sun, Shihui" sort="Sun, Shihui" uniqKey="Sun S" first="Shihui" last="Sun">Shihui Sun</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author><author><name sortKey="Zhou, Yusen" sort="Zhou, Yusen" uniqKey="Zhou Y" first="Yusen" last="Zhou">Yusen Zhou</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071</wicri:regionArea><wicri:noRegion>100071</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</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>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></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Gralinski, Le" uniqKey="Gralinski L">LE Gralinski</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A Assiri</name></author><author><name sortKey="Mcgeer, A" uniqKey="Mcgeer A">A McGeer</name></author><author><name sortKey="Perl, Tm" uniqKey="Perl T">TM Perl</name></author><author><name sortKey="Price, Cs" uniqKey="Price C">CS Price</name></author><author><name sortKey="Al Rabeeah, Aa" uniqKey="Al Rabeeah A">AA Al Rabeeah</name></author><author><name sortKey="Cummings, Da" uniqKey="Cummings 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sortKey="Li, Junfeng" sort="Li, Junfeng" uniqKey="Li J" first="Junfeng" last="Li">Junfeng Li</name><name sortKey="Qiu, Hongjie" sort="Qiu, Hongjie" uniqKey="Qiu H" first="Hongjie" last="Qiu">Hongjie Qiu</name><name sortKey="Sun, Shihui" sort="Sun, Shihui" uniqKey="Sun S" first="Shihui" last="Sun">Shihui Sun</name><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><name sortKey="Yu, Hong" sort="Yu, Hong" uniqKey="Yu H" first="Hong" last="Yu">Hong Yu</name><name sortKey="Zeng, Yang" sort="Zeng, Yang" uniqKey="Zeng Y" first="Yang" last="Zeng">Yang Zeng</name><name sortKey="Zhou, Yusen" sort="Zhou, Yusen" uniqKey="Zhou Y" first="Yusen" last="Zhou">Yusen Zhou</name></country><country name="États-Unis"><noRegion><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name></noRegion><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo 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