Serveur d'exploration MERS

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MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis

Identifieur interne : 000D13 ( Main/Exploration ); précédent : 000D12; suivant : 000D14

MERS-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 :

RBID : PMC:5565963

Descripteurs français

English descriptors

Abstract

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.


Url:
DOI: 10.1128/mBio.00665-17
PubMed: 28830941
PubMed Central: 5565963


Affiliations:


Links toward previous steps (curation, corpus...)


Le document en format XML

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<name sortKey="Beall, Anne" sort="Beall, Anne" uniqKey="Beall A" first="Anne" last="Beall">Anne Beall</name>
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<addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
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<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
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<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
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<name sortKey="Dinnon, Kenneth" sort="Dinnon, Kenneth" uniqKey="Dinnon K" first="Kenneth" last="Dinnon">Kenneth Dinnon</name>
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<addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
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<wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
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<name sortKey="Kocher, Jacob F" sort="Kocher, Jacob F" uniqKey="Kocher J" first="Jacob F." last="Kocher">Jacob F. Kocher</name>
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<addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
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<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
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<name sortKey="Hale, Andrew E" sort="Hale, Andrew E" uniqKey="Hale A" first="Andrew E." last="Hale">Andrew E. Hale</name>
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<addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
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<wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
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<name sortKey="Stratton, Kelly G" sort="Stratton, Kelly G" uniqKey="Stratton K" first="Kelly G." last="Stratton">Kelly G. Stratton</name>
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<addr-line>Pacific Northwest National Laboratory, Richland, Washington, USA</addr-line>
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<country xml:lang="fr">États-Unis</country>
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<name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M." last="Waters">Katrina M. Waters</name>
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<nlm:aff id="aff4">
<addr-line>Pacific Northwest National Laboratory, Richland, Washington, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
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<region type="state">Washington (État)</region>
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</author>
<author>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<affiliation wicri:level="4">
<nlm:aff id="aff2">
<addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
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<affiliation wicri:level="4">
<nlm:aff id="aff3">
<addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
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<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
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<series>
<title level="j">mBio</title>
<idno type="eISSN">2150-7511</idno>
<imprint>
<date when="2017">2017</date>
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<keywords scheme="KwdEn" xml:lang="en">
<term>Animals</term>
<term>Cell Line</term>
<term>Cells, Cultured</term>
<term>Coronavirus Infections (virology)</term>
<term>Epithelial Cells (virology)</term>
<term>Host-Pathogen Interactions</term>
<term>Humans</term>
<term>Inflammation</term>
<term>Interferons (genetics)</term>
<term>Interferons (metabolism)</term>
<term>Mice</term>
<term>Middle East Respiratory Syndrome Coronavirus (genetics)</term>
<term>Middle East Respiratory Syndrome Coronavirus (pathogenicity)</term>
<term>Mutation</term>
<term>NF-kappa B (metabolism)</term>
<term>Open Reading Frames</term>
<term>Reverse Genetics</term>
<term>Signal Transduction</term>
<term>Virus Replication (genetics)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Animaux</term>
<term>Cadres ouverts de lecture</term>
<term>Cellules cultivées</term>
<term>Cellules épithéliales (virologie)</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (pathogénicité)</term>
<term>Facteur de transcription NF-kappa B (métabolisme)</term>
<term>Génétique inverse</term>
<term>Humains</term>
<term>Infections à coronavirus (virologie)</term>
<term>Inflammation</term>
<term>Interactions hôte-pathogène</term>
<term>Interférons (génétique)</term>
<term>Interférons (métabolisme)</term>
<term>Lignée cellulaire</term>
<term>Mutation</term>
<term>Réplication virale (génétique)</term>
<term>Souris</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Interferons</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Interferons</term>
<term>NF-kappa B</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Middle East Respiratory Syndrome Coronavirus</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Interférons</term>
<term>Réplication virale</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Facteur de transcription NF-kappa B</term>
<term>Interférons</term>
</keywords>
<keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en">
<term>Middle East Respiratory Syndrome Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr">
<term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr">
<term>Cellules épithéliales</term>
<term>Infections à coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Epithelial Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Cell Line</term>
<term>Cells, Cultured</term>
<term>Host-Pathogen Interactions</term>
<term>Humans</term>
<term>Inflammation</term>
<term>Mice</term>
<term>Mutation</term>
<term>Open Reading Frames</term>
<term>Reverse Genetics</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Cadres ouverts de lecture</term>
<term>Cellules cultivées</term>
<term>Génétique inverse</term>
<term>Humains</term>
<term>Inflammation</term>
<term>Interactions hôte-pathogène</term>
<term>Lignée cellulaire</term>
<term>Mutation</term>
<term>Souris</term>
<term>Transduction du signal</term>
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<front>
<div type="abstract" xml:lang="en">
<title>ABSTRACT</title>
<p>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.
<italic>In vitro</italic>
replication attenuation also extends to
<italic>in vivo</italic>
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.</p>
</div>
</front>
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<list>
<country>
<li>États-Unis</li>
</country>
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<li>Caroline du Nord</li>
<li>Texas</li>
<li>Washington (État)</li>
</region>
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<li>Chapel Hill (Caroline du Nord)</li>
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<li>Université de Caroline du Nord à Chapel Hill</li>
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