MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis.
Identifieur interne : 000B89 ( PubMed/Curation ); précédent : 000B88; suivant : 000B90MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis.
Auteurs : Vineet D. Menachery [États-Unis] ; Hugh D. Mitchell [États-Unis] ; Adam S. Cockrell [États-Unis] ; Lisa E. Gralinski [États-Unis] ; Boyd L. Yount [États-Unis] ; Rachel L. Graham [États-Unis] ; Eileen T. Mcanarney [États-Unis] ; Madeline G. Douglas [États-Unis] ; Trevor Scobey [États-Unis] ; Anne Beall [États-Unis] ; Kenneth Dinnon [États-Unis] ; Jacob F. Kocher [États-Unis] ; Andrew E. Hale [États-Unis] ; Kelly G. Stratton [États-Unis] ; Katrina M. Waters [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- mBio [ 2150-7511 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux, Cadres ouverts de lecture, Cellules cultivées, Cellules épithéliales (virologie), Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Coronavirus du syndrome respiratoire du Moyen-Orient (pathogénicité), Facteur de transcription NF-kappa B (métabolisme), Génétique inverse, Humains, Infections à coronavirus (virologie), Inflammation, Interactions hôte-pathogène, Interférons (génétique), Interférons (métabolisme), Lignée cellulaire, Mutation, Réplication virale (génétique), Souris, Transduction du signal.
- MESH :
- génétique : Coronavirus du syndrome respiratoire du Moyen-Orient, Interférons, Réplication virale.
- métabolisme : Facteur de transcription NF-kappa B, Interférons.
- pathogénicité : Coronavirus du syndrome respiratoire du Moyen-Orient.
- virologie : Cellules épithéliales, Infections à coronavirus.
- Animaux, Cadres ouverts de lecture, Cellules cultivées, Génétique inverse, Humains, Inflammation, Interactions hôte-pathogène, Lignée cellulaire, Mutation, Souris, Transduction du signal.
English descriptors
- KwdEn :
- Animals, Cell Line, Cells, Cultured, Coronavirus Infections (virology), Epithelial Cells (virology), Host-Pathogen Interactions, Humans, Inflammation, Interferons (genetics), Interferons (metabolism), Mice, Middle East Respiratory Syndrome Coronavirus (genetics), Middle East Respiratory Syndrome Coronavirus (pathogenicity), Mutation, NF-kappa B (metabolism), Open Reading Frames, Reverse Genetics, Signal Transduction, Virus Replication (genetics).
- MESH :
- chemical , genetics : Interferons.
- chemical , metabolism : Interferons, NF-kappa B.
- genetics : Middle East Respiratory Syndrome Coronavirus, Virus Replication.
- pathogenicity : Middle East Respiratory Syndrome Coronavirus.
- virology : Coronavirus Infections, Epithelial Cells.
- Animals, Cell Line, Cells, Cultured, Host-Pathogen Interactions, Humans, Inflammation, Mice, Mutation, Open Reading Frames, Reverse Genetics, Signal Transduction.
Abstract
While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward.IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.
DOI: 10.1128/mBio.00665-17
PubMed: 28830941
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<front><div type="abstract" xml:lang="en">While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. <i>In vitro</i>
replication attenuation also extends to <i>in vivo</i>
models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward.<b>IMPORTANCE</b>
The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.</div>
</front>
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<DateCompleted><Year>2018</Year>
<Month>06</Month>
<Day>14</Day>
</DateCompleted>
<DateRevised><Year>2019</Year>
<Month>12</Month>
<Day>27</Day>
</DateRevised>
<Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2150-7511</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>8</Volume>
<Issue>4</Issue>
<PubDate><Year>2017</Year>
<Month>08</Month>
<Day>22</Day>
</PubDate>
</JournalIssue>
<Title>mBio</Title>
<ISOAbbreviation>mBio</ISOAbbreviation>
</Journal>
<ArticleTitle>MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis.</ArticleTitle>
<ELocationID EIdType="pii" ValidYN="Y">e00665-17</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.1128/mBio.00665-17</ELocationID>
<Abstract><AbstractText>While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. <i>In vitro</i>
replication attenuation also extends to <i>in vivo</i>
models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward.<b>IMPORTANCE</b>
The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.</AbstractText>
<CopyrightInformation>Copyright © 2017 Menachery et al.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Menachery</LastName>
<ForeName>Vineet D</ForeName>
<Initials>VD</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mitchell</LastName>
<ForeName>Hugh D</ForeName>
<Initials>HD</Initials>
<AffiliationInfo><Affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cockrell</LastName>
<ForeName>Adam S</ForeName>
<Initials>AS</Initials>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gralinski</LastName>
<ForeName>Lisa E</ForeName>
<Initials>LE</Initials>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yount</LastName>
<ForeName>Boyd L</ForeName>
<Initials>BL</Initials>
<Suffix>Jr</Suffix>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>Rachel L</ForeName>
<Initials>RL</Initials>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
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<ForeName>Eileen T</ForeName>
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<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>Madeline G</ForeName>
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<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>Trevor</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Beall</LastName>
<ForeName>Anne</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dinnon</LastName>
<ForeName>Kenneth</ForeName>
<Initials>K</Initials>
<Suffix>3rd</Suffix>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kocher</LastName>
<ForeName>Jacob F</ForeName>
<Initials>JF</Initials>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hale</LastName>
<ForeName>Andrew E</ForeName>
<Initials>AE</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Stratton</LastName>
<ForeName>Kelly G</ForeName>
<Initials>KG</Initials>
<AffiliationInfo><Affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Waters</LastName>
<ForeName>Katrina M</ForeName>
<Initials>KM</Initials>
<AffiliationInfo><Affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Baric</LastName>
<ForeName>Ralph S</ForeName>
<Initials>RS</Initials>
<AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Rbaric@email.unc.edu.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>R00 AG049092</GrantID>
<Acronym>AG</Acronym>
<Agency>NIA NIH HHS</Agency>
<Country>United States</Country>
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<Acronym>AI</Acronym>
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<Country>United States</Country>
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</MeshHeading>
<MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName>
</MeshHeading>
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</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D065207" MajorTopicYN="N">Middle East Respiratory Syndrome Coronavirus</DescriptorName>
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<Keyword MajorTopicYN="Y">live vector vaccines</Keyword>
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