A Human DPP4-Knockin Mouse’s Susceptibility to Infection by Authentic and Pseudotyped MERS-CoV
Identifieur interne : 000739 ( Main/Exploration ); précédent : 000738; suivant : 000740A Human DPP4-Knockin Mouse’s Susceptibility to Infection by Authentic and Pseudotyped MERS-CoV
Auteurs : Changfa Fan ; Xi Wu ; Qiang Liu ; Qianqian Li ; Susu Liu ; Jianjun Lu ; Yanwei Yang ; Yuan Cao ; Weijin Huang ; Chunnan Liang ; Tianlei Ying ; Shibo Jiang ; Youchun WangSource :
- Viruses [ 1999-4915 ] ; 2018.
Abstract
Infection by the Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory illness and has a high mortality rate (~35%). The requirement for the virus to be manipulated in a biosafety level three (BSL-3) facility has impeded development of urgently-needed antiviral agents. Here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hDPP4) into the Rosa26 locus using CRISPR/Cas9, resulting in global expression of the transgene in a genetically stable mouse line. The mice were highly susceptible to infection by MERS-CoV clinical strain hCoV-EMC, which induced severe diffuse pulmonary disease in the animals, and could also be infected by an optimized pseudotyped MERS-CoV. Administration of the neutralizing monoclonal antibodies, H111-1 and m336, as well as a fusion inhibitor peptide, HR2P-M2, protected mice from challenge with authentic and pseudotyped MERS-CoV. These results confirmed that the hDPP4-knockin mouse is a novel model for studies of MERS-CoV pathogenesis and anti-MERS-CoV antiviral agents in BSL-3 and BSL-2facilities, respectively.
Url:
DOI: 10.3390/v10090448
PubMed: 30142928
PubMed Central: 6164841
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Human DPP4-Knockin Mouse’s Susceptibility to Infection by Authentic and Pseudotyped MERS-CoV</title><author><name sortKey="Fan, Changfa" sort="Fan, Changfa" uniqKey="Fan C" first="Changfa" last="Fan">Changfa Fan</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Wu, Xi" sort="Wu, Xi" uniqKey="Wu X" first="Xi" last="Wu">Xi Wu</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Qiang" sort="Liu, Qiang" uniqKey="Liu Q" first="Qiang" last="Liu">Qiang Liu</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author><author><name sortKey="Li, Qianqian" sort="Li, Qianqian" uniqKey="Li Q" first="Qianqian" last="Li">Qianqian Li</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Susu" sort="Liu, Susu" uniqKey="Liu S" first="Susu" last="Liu">Susu Liu</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Lu, Jianjun" sort="Lu, Jianjun" uniqKey="Lu J" first="Jianjun" last="Lu">Jianjun Lu</name><affiliation><nlm:aff id="af3-viruses-10-00448">National Center for Safety Evaluation of Drugs, Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China;<email>lujianjun@nifdc.org.cn</email> (J.L.);<email>yangyanwei@nifdc.org.cn</email> (Y.Y.)</nlm:aff></affiliation></author><author><name sortKey="Yang, Yanwei" sort="Yang, Yanwei" uniqKey="Yang Y" first="Yanwei" last="Yang">Yanwei Yang</name><affiliation><nlm:aff id="af3-viruses-10-00448">National Center for Safety Evaluation of Drugs, Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China;<email>lujianjun@nifdc.org.cn</email> (J.L.);<email>yangyanwei@nifdc.org.cn</email> (Y.Y.)</nlm:aff></affiliation></author><author><name sortKey="Cao, Yuan" sort="Cao, Yuan" uniqKey="Cao Y" first="Yuan" last="Cao">Yuan Cao</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Huang, Weijin" sort="Huang, Weijin" uniqKey="Huang W" first="Weijin" last="Huang">Weijin Huang</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author><author><name sortKey="Liang, Chunnan" sort="Liang, Chunnan" uniqKey="Liang C" first="Chunnan" last="Liang">Chunnan Liang</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Ying, Tianlei" sort="Ying, Tianlei" uniqKey="Ying T" first="Tianlei" last="Ying">Tianlei Ying</name><affiliation><nlm:aff id="af4-viruses-10-00448">Key Laboratory of Medical Molecular Virology of the Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai 200032, China;<email>tlying@fudan.edu.cn</email> (T.Y.);<email>shibojiang@fudan.edu.cn</email> (S.J.)</nlm:aff></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation><nlm:aff id="af4-viruses-10-00448">Key Laboratory of Medical Molecular Virology of the Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai 200032, China;<email>tlying@fudan.edu.cn</email> (T.Y.);<email>shibojiang@fudan.edu.cn</email> (S.J.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Youchun" sort="Wang, Youchun" uniqKey="Wang Y" first="Youchun" last="Wang">Youchun Wang</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30142928</idno><idno type="pmc">6164841</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164841</idno><idno type="RBID">PMC:6164841</idno><idno type="doi">10.3390/v10090448</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000736</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000736</idno><idno type="wicri:Area/Pmc/Curation">000736</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000736</idno><idno type="wicri:Area/Pmc/Checkpoint">000158</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000158</idno><idno type="wicri:Area/Ncbi/Merge">000722</idno><idno type="wicri:Area/Ncbi/Curation">000722</idno><idno type="wicri:Area/Ncbi/Checkpoint">000722</idno><idno type="wicri:Area/Main/Merge">000741</idno><idno type="wicri:Area/Main/Curation">000739</idno><idno type="wicri:Area/Main/Exploration">000739</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Human DPP4-Knockin Mouse’s Susceptibility to Infection by Authentic and Pseudotyped MERS-CoV</title><author><name sortKey="Fan, Changfa" sort="Fan, Changfa" uniqKey="Fan C" first="Changfa" last="Fan">Changfa Fan</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Wu, Xi" sort="Wu, Xi" uniqKey="Wu X" first="Xi" last="Wu">Xi Wu</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Qiang" sort="Liu, Qiang" uniqKey="Liu Q" first="Qiang" last="Liu">Qiang Liu</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author><author><name sortKey="Li, Qianqian" sort="Li, Qianqian" uniqKey="Li Q" first="Qianqian" last="Li">Qianqian Li</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Susu" sort="Liu, Susu" uniqKey="Liu S" first="Susu" last="Liu">Susu Liu</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Lu, Jianjun" sort="Lu, Jianjun" uniqKey="Lu J" first="Jianjun" last="Lu">Jianjun Lu</name><affiliation><nlm:aff id="af3-viruses-10-00448">National Center for Safety Evaluation of Drugs, Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China;<email>lujianjun@nifdc.org.cn</email> (J.L.);<email>yangyanwei@nifdc.org.cn</email> (Y.Y.)</nlm:aff></affiliation></author><author><name sortKey="Yang, Yanwei" sort="Yang, Yanwei" uniqKey="Yang Y" first="Yanwei" last="Yang">Yanwei Yang</name><affiliation><nlm:aff id="af3-viruses-10-00448">National Center for Safety Evaluation of Drugs, Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China;<email>lujianjun@nifdc.org.cn</email> (J.L.);<email>yangyanwei@nifdc.org.cn</email> (Y.Y.)</nlm:aff></affiliation></author><author><name sortKey="Cao, Yuan" sort="Cao, Yuan" uniqKey="Cao Y" first="Yuan" last="Cao">Yuan Cao</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Huang, Weijin" sort="Huang, Weijin" uniqKey="Huang W" first="Weijin" last="Huang">Weijin Huang</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author><author><name sortKey="Liang, Chunnan" sort="Liang, Chunnan" uniqKey="Liang C" first="Chunnan" last="Liang">Chunnan Liang</name><affiliation><nlm:aff id="af1-viruses-10-00448">Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China;<email>fancf@nifdc.org.cn</email> (C.F.);<email>wuxi@nifdc.org.cn</email> (X.W.);<email>liususu@nifdc.org.cn</email> (S.L.);<email>caoyuan0512@163.com</email> (Y.C.);<email>chunnan_liang@nifdc.org.cn</email> (C.L.)</nlm:aff></affiliation></author><author><name sortKey="Ying, Tianlei" sort="Ying, Tianlei" uniqKey="Ying T" first="Tianlei" last="Ying">Tianlei Ying</name><affiliation><nlm:aff id="af4-viruses-10-00448">Key Laboratory of Medical Molecular Virology of the Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai 200032, China;<email>tlying@fudan.edu.cn</email> (T.Y.);<email>shibojiang@fudan.edu.cn</email> (S.J.)</nlm:aff></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation><nlm:aff id="af4-viruses-10-00448">Key Laboratory of Medical Molecular Virology of the Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai 200032, China;<email>tlying@fudan.edu.cn</email> (T.Y.);<email>shibojiang@fudan.edu.cn</email> (S.J.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Youchun" sort="Wang, Youchun" uniqKey="Wang Y" first="Youchun" last="Wang">Youchun Wang</name><affiliation><nlm:aff id="af2-viruses-10-00448">Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China;<email>liuqiang@nifdc.org.cn</email> (Q.L.);<email>liqianqian1199@163.com</email> (Q.L.);<email>huangweijin@nifdc.org.cn</email> (W.H.)</nlm:aff></affiliation></author></analytic><series><title level="j">Viruses</title><idno type="eISSN">1999-4915</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Infection by the Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory illness and has a high mortality rate (~35%). The requirement for the virus to be manipulated in a biosafety level three (BSL-3) facility has impeded development of urgently-needed antiviral agents. Here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hDPP4) into the Rosa26 locus using CRISPR/Cas9, resulting in global expression of the transgene in a genetically stable mouse line. The mice were highly susceptible to infection by MERS-CoV clinical strain hCoV-EMC, which induced severe diffuse pulmonary disease in the animals, and could also be infected by an optimized pseudotyped MERS-CoV. Administration of the neutralizing monoclonal antibodies, H111-1 and m336, as well as a fusion inhibitor peptide, HR2P-M2, protected mice from challenge with authentic and pseudotyped MERS-CoV. These results confirmed that the hDPP4-knockin mouse is a novel model for studies of MERS-CoV pathogenesis and anti-MERS-CoV antiviral agents in BSL-3 and BSL-2facilities, respectively.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Du, L" uniqKey="Du L">L. Du</name></author><author><name sortKey="Zhao, G" uniqKey="Zhao G">G. Zhao</name></author><author><name sortKey="Chan, C C" uniqKey="Chan C">C.C. Chan</name></author><author><name sortKey="Sun, S" uniqKey="Sun S">S. Sun</name></author><author><name sortKey="Chen, M" uniqKey="Chen M">M. Chen</name></author><author><name sortKey="Liu, Z" uniqKey="Liu Z">Z. Liu</name></author><author><name sortKey="Guo, H" uniqKey="Guo H">H. Guo</name></author><author><name sortKey="He, Y" uniqKey="He Y">Y. He</name></author><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y. Zhou</name></author><author><name sortKey="Zheng, B J" uniqKey="Zheng B">B.-J. 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