MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment.
Identifieur interne : 001145 ( PubMed/Checkpoint ); précédent : 001144; suivant : 001146MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment.
Auteurs : Adriaan H. De Wilde [Pays-Bas] ; V Stalin Raj [Pays-Bas] ; Diede Oudshoorn [Pays-Bas] ; Theo M. Bestebroer [Pays-Bas] ; Stefan Van Nieuwkoop [Pays-Bas] ; Ronald W A L. Limpens [Pays-Bas] ; Clara C. Posthuma [Pays-Bas] ; Yvonne Van Der Meer [Pays-Bas] ; Montserrat Bárcena [Pays-Bas] ; Bart L. Haagmans [Pays-Bas] ; Eric J. Snijder [Pays-Bas] ; Bernadette G. Van Den Hoogen [Pays-Bas]Source :
- The Journal of general virology [ 1465-2099 ] ; 2013.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (pharmacologie), Ciclosporine (pharmacologie), Coronavirus (), Coronavirus (pathogénicité), Coronavirus (physiologie), Effet cytopathogène viral, Humains, Interféron alpha (pharmacologie), Lignée cellulaire, Membrane cellulaire (ultrastructure), Microscopie électronique à transmission, Réplication virale, Tests de sensibilité microbienne, Évaluation préclinique de médicament.
- MESH :
- pathogénicité : Coronavirus.
- pharmacologie : Antiviraux, Ciclosporine, Interféron alpha.
- physiologie : Coronavirus.
- Animaux, Coronavirus, Effet cytopathogène viral, Humains, Lignée cellulaire, Membrane cellulaire, Microscopie électronique à transmission, Réplication virale, Tests de sensibilité microbienne, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (pharmacology), Cell Line, Cell Membrane (ultrastructure), Chlorocebus aethiops, Coronavirus (drug effects), Coronavirus (pathogenicity), Coronavirus (physiology), Cyclosporine (pharmacology), Cytopathogenic Effect, Viral, Drug Evaluation, Preclinical, Humans, Interferon-alpha (pharmacology), Microbial Sensitivity Tests, Microscopy, Electron, Transmission, Virus Replication.
- MESH :
- chemical , pharmacology : Antiviral Agents, Cyclosporine, Interferon-alpha.
- drug effects : Coronavirus.
- pathogenicity : Coronavirus.
- physiology : Coronavirus.
- ultrastructure : Cell Membrane.
- Animals, Cell Line, Chlorocebus aethiops, Cytopathogenic Effect, Viral, Drug Evaluation, Preclinical, Humans, Microbial Sensitivity Tests, Microscopy, Electron, Transmission, Virus Replication.
Abstract
Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. The 2003 outbreak of severe acute respiratory syndrome (SARS) highlighted the potentially lethal consequences of CoV-induced disease in humans. In 2012, a novel CoV (Middle East Respiratory Syndrome coronavirus; MERS-CoV) emerged, causing 49 human cases thus far, of which 23 had a fatal outcome. In this study, we characterized MERS-CoV replication and cytotoxicity in human and monkey cell lines. Electron microscopy of infected Vero cells revealed extensive membrane rearrangements, including the formation of double-membrane vesicles and convoluted membranes, which have been implicated previously in the RNA synthesis of SARS-CoV and other CoVs. Following infection, we observed rapidly increasing viral RNA synthesis and release of high titres of infectious progeny, followed by a pronounced cytopathology. These characteristics were used to develop an assay for antiviral compound screening in 96-well format, which was used to identify cyclosporin A as an inhibitor of MERS-CoV replication in cell culture. Furthermore, MERS-CoV was found to be 50-100 times more sensitive to alpha interferon (IFN-α) treatment than SARS-CoV, an observation that may have important implications for the treatment of MERS-CoV-infected patients. MERS-CoV infection did not prevent the IFN-induced nuclear translocation of phosphorylated STAT1, in contrast to infection with SARS-CoV where this block inhibits the expression of antiviral genes. These findings highlight relevant differences between these distantly related zoonotic CoVs in terms of their interaction with and evasion of the cellular innate immune response.
DOI: 10.1099/vir.0.052910-0
PubMed: 23620378
Affiliations:
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Limpens</name><affiliation wicri:level="3"><nlm:affiliation>Section Electron Microscopy, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Section Electron Microscopy, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Posthuma, Clara C" sort="Posthuma, Clara C" uniqKey="Posthuma C" first="Clara C" last="Posthuma">Clara C. Posthuma</name><affiliation wicri:level="3"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Van Der Meer, Yvonne" sort="Van Der Meer, Yvonne" uniqKey="Van Der Meer Y" first="Yvonne" last="Van Der Meer">Yvonne Van Der Meer</name><affiliation wicri:level="3"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Barcena, Montserrat" sort="Barcena, Montserrat" uniqKey="Barcena M" first="Montserrat" last="Bárcena">Montserrat Bárcena</name><affiliation wicri:level="3"><nlm:affiliation>Section Electron Microscopy, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Section Electron Microscopy, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Haagmans, Bart L" sort="Haagmans, Bart L" uniqKey="Haagmans B" first="Bart L" last="Haagmans">Bart L. Haagmans</name><affiliation wicri:level="3"><nlm:affiliation>Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Viroscience Lab, Erasmus MC, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><affiliation wicri:level="3"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Van Den Hoogen, Bernadette G" sort="Van Den Hoogen, Bernadette G" uniqKey="Van Den Hoogen B" first="Bernadette G" last="Van Den Hoogen">Bernadette G. Van Den Hoogen</name><affiliation wicri:level="3"><nlm:affiliation>Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Viroscience Lab, Erasmus MC, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of general virology</title><idno type="eISSN">1465-2099</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Cell Membrane (ultrastructure)</term><term>Chlorocebus aethiops</term><term>Coronavirus (drug effects)</term><term>Coronavirus (pathogenicity)</term><term>Coronavirus (physiology)</term><term>Cyclosporine (pharmacology)</term><term>Cytopathogenic Effect, Viral</term><term>Drug Evaluation, Preclinical</term><term>Humans</term><term>Interferon-alpha (pharmacology)</term><term>Microbial Sensitivity Tests</term><term>Microscopy, Electron, Transmission</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Ciclosporine (pharmacologie)</term><term>Coronavirus ()</term><term>Coronavirus (pathogénicité)</term><term>Coronavirus (physiologie)</term><term>Effet cytopathogène viral</term><term>Humains</term><term>Interféron alpha (pharmacologie)</term><term>Lignée cellulaire</term><term>Membrane cellulaire (ultrastructure)</term><term>Microscopie électronique à transmission</term><term>Réplication virale</term><term>Tests de sensibilité microbienne</term><term>Évaluation préclinique de médicament</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Cyclosporine</term><term>Interferon-alpha</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Ciclosporine</term><term>Interféron alpha</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Cell Membrane</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Chlorocebus aethiops</term><term>Cytopathogenic Effect, Viral</term><term>Drug Evaluation, Preclinical</term><term>Humans</term><term>Microbial Sensitivity Tests</term><term>Microscopy, Electron, Transmission</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Coronavirus</term><term>Effet cytopathogène viral</term><term>Humains</term><term>Lignée cellulaire</term><term>Membrane cellulaire</term><term>Microscopie électronique à transmission</term><term>Réplication virale</term><term>Tests de sensibilité microbienne</term><term>Évaluation préclinique de médicament</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. The 2003 outbreak of severe acute respiratory syndrome (SARS) highlighted the potentially lethal consequences of CoV-induced disease in humans. In 2012, a novel CoV (Middle East Respiratory Syndrome coronavirus; MERS-CoV) emerged, causing 49 human cases thus far, of which 23 had a fatal outcome. In this study, we characterized MERS-CoV replication and cytotoxicity in human and monkey cell lines. Electron microscopy of infected Vero cells revealed extensive membrane rearrangements, including the formation of double-membrane vesicles and convoluted membranes, which have been implicated previously in the RNA synthesis of SARS-CoV and other CoVs. Following infection, we observed rapidly increasing viral RNA synthesis and release of high titres of infectious progeny, followed by a pronounced cytopathology. These characteristics were used to develop an assay for antiviral compound screening in 96-well format, which was used to identify cyclosporin A as an inhibitor of MERS-CoV replication in cell culture. Furthermore, MERS-CoV was found to be 50-100 times more sensitive to alpha interferon (IFN-α) treatment than SARS-CoV, an observation that may have important implications for the treatment of MERS-CoV-infected patients. MERS-CoV infection did not prevent the IFN-induced nuclear translocation of phosphorylated STAT1, in contrast to infection with SARS-CoV where this block inhibits the expression of antiviral genes. These findings highlight relevant differences between these distantly related zoonotic CoVs in terms of their interaction with and evasion of the cellular innate immune response. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">23620378</PMID><DateCompleted><Year>2013</Year><Month>09</Month><Day>24</Day></DateCompleted><DateRevised><Year>2020</Year><Month>03</Month><Day>05</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1465-2099</ISSN><JournalIssue CitedMedium="Internet"><Volume>94</Volume><Issue>Pt 8</Issue><PubDate><Year>2013</Year><Month>Aug</Month></PubDate></JournalIssue><Title>The Journal of general virology</Title><ISOAbbreviation>J. Gen. Virol.</ISOAbbreviation></Journal><ArticleTitle>MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment.</ArticleTitle><Pagination><MedlinePgn>1749-1760</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1099/vir.0.052910-0</ELocationID><Abstract><AbstractText>Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. The 2003 outbreak of severe acute respiratory syndrome (SARS) highlighted the potentially lethal consequences of CoV-induced disease in humans. In 2012, a novel CoV (Middle East Respiratory Syndrome coronavirus; MERS-CoV) emerged, causing 49 human cases thus far, of which 23 had a fatal outcome. In this study, we characterized MERS-CoV replication and cytotoxicity in human and monkey cell lines. Electron microscopy of infected Vero cells revealed extensive membrane rearrangements, including the formation of double-membrane vesicles and convoluted membranes, which have been implicated previously in the RNA synthesis of SARS-CoV and other CoVs. Following infection, we observed rapidly increasing viral RNA synthesis and release of high titres of infectious progeny, followed by a pronounced cytopathology. These characteristics were used to develop an assay for antiviral compound screening in 96-well format, which was used to identify cyclosporin A as an inhibitor of MERS-CoV replication in cell culture. Furthermore, MERS-CoV was found to be 50-100 times more sensitive to alpha interferon (IFN-α) treatment than SARS-CoV, an observation that may have important implications for the treatment of MERS-CoV-infected patients. MERS-CoV infection did not prevent the IFN-induced nuclear translocation of phosphorylated STAT1, in contrast to infection with SARS-CoV where this block inhibits the expression of antiviral genes. These findings highlight relevant differences between these distantly related zoonotic CoVs in terms of their interaction with and evasion of the cellular innate immune response. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>de Wilde</LastName><ForeName>Adriaan H</ForeName><Initials>AH</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Raj</LastName><ForeName>V Stalin</ForeName><Initials>VS</Initials><AffiliationInfo><Affiliation>Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Oudshoorn</LastName><ForeName>Diede</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bestebroer</LastName><ForeName>Theo M</ForeName><Initials>TM</Initials><AffiliationInfo><Affiliation>Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Nieuwkoop</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Limpens</LastName><ForeName>Ronald W A L</ForeName><Initials>RWAL</Initials><AffiliationInfo><Affiliation>Section Electron Microscopy, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Posthuma</LastName><ForeName>Clara C</ForeName><Initials>CC</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van der Meer</LastName><ForeName>Yvonne</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bárcena</LastName><ForeName>Montserrat</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Section Electron Microscopy, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haagmans</LastName><ForeName>Bart L</ForeName><Initials>BL</Initials><AffiliationInfo><Affiliation>Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Snijder</LastName><ForeName>Eric J</ForeName><Initials>EJ</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van den Hoogen</LastName><ForeName>Bernadette G</ForeName><Initials>BG</Initials><AffiliationInfo><Affiliation>Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2013</Year><Month>04</Month><Day>25</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Gen Virol</MedlineTA><NlmUniqueID>0077340</NlmUniqueID><ISSNLinking>0022-1317</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016898">Interferon-alpha</NameOfSubstance></Chemical><Chemical><RegistryNumber>83HN0GTJ6D</RegistryNumber><NameOfSubstance UI="D016572">Cyclosporine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002462" MajorTopicYN="N">Cell 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