Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice.
Identifieur interne : 000C70 ( Main/Exploration ); précédent : 000C69; suivant : 000C71Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice.
Auteurs : Kun Li [États-Unis] ; Christine L. Wohlford-Lenane [États-Unis] ; Rudragouda Channappanavar [États-Unis] ; Jung-Eun Park [États-Unis] ; James T. Earnest [États-Unis] ; Thomas B. Bair [États-Unis] ; Amber M. Bates [États-Unis] ; Kim A. Brogden [États-Unis] ; Heather A. Flaherty [États-Unis] ; Tom Gallagher [États-Unis] ; David K. Meyerholz [États-Unis] ; Stanley Perlman [États-Unis] ; Paul B. Mccray [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux, Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Dipeptidyl peptidase 4 (génétique), Dipeptidyl peptidase 4 (métabolisme), Femelle, Glycoprotéine de spicule des coronavirus (génétique), Humains, Infections à coronavirus (), Infections à coronavirus (virologie), Maladies pulmonaires (anatomopathologie), Maladies pulmonaires (métabolisme), Maladies pulmonaires (étiologie), Modèles animaux de maladie humaine, Mutation, Mâle, Réplication virale, Souris, Souris de lignée C57BL.
- MESH :
- anatomopathologie : Maladies pulmonaires.
- génétique : Coronavirus du syndrome respiratoire du Moyen-Orient, Dipeptidyl peptidase 4, Glycoprotéine de spicule des coronavirus.
- métabolisme : Dipeptidyl peptidase 4, Maladies pulmonaires.
- virologie : Infections à coronavirus.
- étiologie : Maladies pulmonaires.
- Animaux, Femelle, Humains, Infections à coronavirus, Modèles animaux de maladie humaine, Mutation, Mâle, Réplication virale, Souris, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Animals, Coronavirus Infections (complications), Coronavirus Infections (virology), Dipeptidyl Peptidase 4 (genetics), Dipeptidyl Peptidase 4 (metabolism), Disease Models, Animal, Female, Humans, Lung Diseases (etiology), Lung Diseases (metabolism), Lung Diseases (pathology), Male, Mice, Mice, Inbred C57BL, Middle East Respiratory Syndrome Coronavirus (genetics), Mutation, Spike Glycoprotein, Coronavirus (genetics), Virus Replication.
- MESH :
- chemical , genetics : Dipeptidyl Peptidase 4, Spike Glycoprotein, Coronavirus.
- complications : Coronavirus Infections.
- etiology : Lung Diseases.
- genetics : Middle East Respiratory Syndrome Coronavirus.
- chemical , metabolism : Dipeptidyl Peptidase 4, Lung Diseases.
- pathology : Lung Diseases.
- virology : Coronavirus Infections.
- Animals, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Virus Replication.
Abstract
The Middle East respiratory syndrome (MERS) emerged in Saudi Arabia in 2012, caused by a zoonotically transmitted coronavirus (CoV). Over 1,900 cases have been reported to date, with ∼36% fatality rate. Lack of autopsies from MERS cases has hindered understanding of MERS-CoV pathogenesis. A small animal model that develops progressive pulmonary manifestations when infected with MERS-CoV would advance the field. As mice are restricted to infection at the level of DPP4, the MERS-CoV receptor, we generated mice with humanized exons 10-12 of the mouse Dpp4 locus. Upon inoculation with MERS-CoV, human DPP4 knockin (KI) mice supported virus replication in the lungs, but developed no illness. After 30 serial passages through the lungs of KI mice, a mouse-adapted virus emerged (MERSMA) that grew in lungs to over 100 times higher titers than the starting virus. A plaque-purified MERSMA clone caused weight loss and fatal infection. Virus antigen was observed in airway epithelia, pneumocytes, and macrophages. Pathologic findings included diffuse alveolar damage with pulmonary edema and hyaline membrane formation associated with accumulation of activated inflammatory monocyte-macrophages and neutrophils in the lungs. Relative to the parental MERS-CoV, MERSMA viruses contained 13-22 mutations, including several within the spike (S) glycoprotein gene. S-protein mutations sensitized viruses to entry-activating serine proteases and conferred more rapid entry kinetics. Recombinant MERSMA bearing mutant S proteins were more virulent than the parental virus in hDPP4 KI mice. The hDPP4 KI mouse and the MERSMA provide tools to investigate disease causes and develop new therapies.
DOI: 10.1073/pnas.1619109114
PubMed: 28348219
Affiliations:
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Wohlford-Lenane</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City</wicri:cityArea></affiliation></author><author><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, University of Iowa, Iowa City, IA 52242.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>Department of Microbiology, University of Iowa, Iowa City</wicri:cityArea></affiliation></author><author><name sortKey="Park, Jung Eun" sort="Park, Jung Eun" uniqKey="Park J" first="Jung-Eun" last="Park">Jung-Eun Park</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, Loyola University Chicago, Maywood</wicri:cityArea></affiliation></author><author><name sortKey="Earnest, James T" sort="Earnest, James T" uniqKey="Earnest J" first="James T" last="Earnest">James T. Earnest</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, Loyola University Chicago, Maywood</wicri:cityArea></affiliation></author><author><name sortKey="Bair, Thomas B" sort="Bair, Thomas B" uniqKey="Bair T" first="Thomas B" last="Bair">Thomas B. Bair</name><affiliation wicri:level="2"><nlm:affiliation>Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA 52242.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>Iowa Institute of Human Genetics, University of Iowa, Iowa City</wicri:cityArea></affiliation></author><author><name sortKey="Bates, Amber M" sort="Bates, Amber M" uniqKey="Bates A" first="Amber M" last="Bates">Amber M. Bates</name><affiliation wicri:level="2"><nlm:affiliation>College of Dentistry, University of Iowa, Iowa City, IA 52242.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>College of Dentistry, University of Iowa, Iowa City</wicri:cityArea></affiliation></author><author><name sortKey="Brogden, Kim A" sort="Brogden, Kim A" uniqKey="Brogden K" first="Kim A" last="Brogden">Kim A. Brogden</name><affiliation wicri:level="2"><nlm:affiliation>College of Dentistry, University of Iowa, Iowa City, IA 52242.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>College of Dentistry, University of Iowa, Iowa City</wicri:cityArea></affiliation></author><author><name sortKey="Flaherty, Heather A" sort="Flaherty, Heather A" uniqKey="Flaherty H" first="Heather A" last="Flaherty">Heather A. Flaherty</name><affiliation wicri:level="2"><nlm:affiliation>Department of Veterinary Pathology, Iowa State University, Ames, IA 50011.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>Department of Veterinary Pathology, Iowa State University, Ames</wicri:cityArea></affiliation></author><author><name sortKey="Gallagher, Tom" sort="Gallagher, Tom" uniqKey="Gallagher T" first="Tom" last="Gallagher">Tom Gallagher</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, Loyola University Chicago, Maywood</wicri:cityArea></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 wicri:level="2"><nlm:affiliation>Department of Pathology, University of Iowa, Iowa City, IA 52242.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>Department of Pathology, University of Iowa, Iowa City</wicri:cityArea></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Iowa</region></placeName><wicri:cityArea>Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City</wicri:cityArea></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 wicri:level="4"><nlm:affiliation>Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242; paul-mccray@uiowa.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City</wicri:regionArea><orgName type="university">Université de l'Iowa</orgName><placeName><settlement type="city">Iowa City</settlement><region type="state">Iowa</region></placeName></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Coronavirus Infections (complications)</term><term>Coronavirus Infections (virology)</term><term>Dipeptidyl Peptidase 4 (genetics)</term><term>Dipeptidyl Peptidase 4 (metabolism)</term><term>Disease Models, Animal</term><term>Female</term><term>Humans</term><term>Lung Diseases (etiology)</term><term>Lung Diseases (metabolism)</term><term>Lung Diseases (pathology)</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Middle East Respiratory Syndrome Coronavirus (genetics)</term><term>Mutation</term><term>Spike Glycoprotein, Coronavirus (genetics)</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term><term>Dipeptidyl peptidase 4 (génétique)</term><term>Dipeptidyl peptidase 4 (métabolisme)</term><term>Femelle</term><term>Glycoprotéine de spicule des coronavirus (génétique)</term><term>Humains</term><term>Infections à coronavirus ()</term><term>Infections à coronavirus (virologie)</term><term>Maladies pulmonaires (anatomopathologie)</term><term>Maladies pulmonaires (métabolisme)</term><term>Maladies pulmonaires (étiologie)</term><term>Modèles animaux de maladie humaine</term><term>Mutation</term><term>Mâle</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée C57BL</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Dipeptidyl Peptidase 4</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Maladies pulmonaires</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Lung Diseases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Dipeptidyl peptidase 4</term><term>Glycoprotéine de spicule des coronavirus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dipeptidyl Peptidase 4</term><term>Lung Diseases</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Dipeptidyl peptidase 4</term><term>Maladies pulmonaires</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung Diseases</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="étiologie" xml:lang="fr"><term>Maladies pulmonaires</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Humans</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mutation</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Femelle</term><term>Humains</term><term>Infections à coronavirus</term><term>Modèles animaux de maladie humaine</term><term>Mutation</term><term>Mâle</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée C57BL</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The Middle East respiratory syndrome (MERS) emerged in Saudi Arabia in 2012, caused by a zoonotically transmitted coronavirus (CoV). Over 1,900 cases have been reported to date, with ∼36% fatality rate. Lack of autopsies from MERS cases has hindered understanding of MERS-CoV pathogenesis. A small animal model that develops progressive pulmonary manifestations when infected with MERS-CoV would advance the field. As mice are restricted to infection at the level of DPP4, the MERS-CoV receptor, we generated mice with humanized exons 10-12 of the mouse <i>Dpp4</i> locus. Upon inoculation with MERS-CoV, human DPP4 knockin (KI) mice supported virus replication in the lungs, but developed no illness. After 30 serial passages through the lungs of KI mice, a mouse-adapted virus emerged (MERS<sub>MA</sub>) that grew in lungs to over 100 times higher titers than the starting virus. A plaque-purified MERS<sub>MA</sub> clone caused weight loss and fatal infection. Virus antigen was observed in airway epithelia, pneumocytes, and macrophages. Pathologic findings included diffuse alveolar damage with pulmonary edema and hyaline membrane formation associated with accumulation of activated inflammatory monocyte-macrophages and neutrophils in the lungs. Relative to the parental MERS-CoV, MERS<sub>MA</sub> viruses contained 13-22 mutations, including several within the spike (S) glycoprotein gene. S-protein mutations sensitized viruses to entry-activating serine proteases and conferred more rapid entry kinetics. Recombinant MERS<sub>MA</sub> bearing mutant S proteins were more virulent than the parental virus in hDPP4 KI mice. The hDPP4 KI mouse and the MERS<sub>MA</sub> provide tools to investigate disease causes and develop new therapies.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li><li>Iowa</li></region><settlement><li>Iowa City</li></settlement><orgName><li>Université de l'Iowa</li></orgName></list><tree><country name="États-Unis"><region name="Iowa"><name sortKey="Li, Kun" sort="Li, Kun" uniqKey="Li K" first="Kun" last="Li">Kun Li</name></region><name sortKey="Bair, Thomas B" sort="Bair, Thomas B" uniqKey="Bair T" first="Thomas B" last="Bair">Thomas B. Bair</name><name sortKey="Bates, Amber M" sort="Bates, Amber M" uniqKey="Bates A" first="Amber M" last="Bates">Amber M. Bates</name><name sortKey="Brogden, Kim A" sort="Brogden, Kim A" uniqKey="Brogden K" first="Kim A" last="Brogden">Kim A. Brogden</name><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name><name sortKey="Earnest, James T" sort="Earnest, James T" uniqKey="Earnest J" first="James T" last="Earnest">James T. Earnest</name><name sortKey="Flaherty, Heather A" sort="Flaherty, Heather A" uniqKey="Flaherty H" first="Heather A" last="Flaherty">Heather A. Flaherty</name><name sortKey="Gallagher, Tom" sort="Gallagher, Tom" uniqKey="Gallagher T" first="Tom" last="Gallagher">Tom Gallagher</name><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B" last="Mccray">Paul B. Mccray</name><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K" last="Meyerholz">David K. Meyerholz</name><name sortKey="Park, Jung Eun" sort="Park, Jung Eun" uniqKey="Park J" first="Jung-Eun" last="Park">Jung-Eun Park</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><name sortKey="Wohlford Lenane, Christine L" sort="Wohlford Lenane, Christine L" uniqKey="Wohlford Lenane C" first="Christine L" last="Wohlford-Lenane">Christine L. Wohlford-Lenane</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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