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Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.

Identifieur interne : 000B57 ( PubMed/Corpus ); précédent : 000B56; suivant : 000B58

Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.

Auteurs : Eveline Kindler ; Cristina Gil-Cruz ; Julia Spanier ; Yize Li ; Jochen Wilhelm ; Huib H. Rabouw ; Roland Züst ; Mihyun Hwang ; Philip V'Kovski ; Hanspeter Stalder ; Sabrina Marti ; Matthias Habjan ; Luisa Cervantes-Barragan ; Ruth Elliot ; Nadja Karl ; Christina Gaughan ; Frank J M. Van Kuppeveld ; Robert H. Silverman ; Markus Keller ; Burkhard Ludewig ; Cornelia C. Bergmann ; John Ziebuhr ; Susan R. Weiss ; Ulrich Kalinke ; Volker Thiel

Source :

RBID : pubmed:28158275

English descriptors

Abstract

Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.

DOI: 10.1371/journal.ppat.1006195
PubMed: 28158275

Links to Exploration step

pubmed:28158275

Le document en format XML

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<name sortKey="Habjan, Matthias" sort="Habjan, Matthias" uniqKey="Habjan M" first="Matthias" last="Habjan">Matthias Habjan</name>
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<nlm:affiliation>Max-Planck-Institute of Biochemistry, Martinsried, Germany.</nlm:affiliation>
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<name sortKey="Cervantes Barragan, Luisa" sort="Cervantes Barragan, Luisa" uniqKey="Cervantes Barragan L" first="Luisa" last="Cervantes-Barragan">Luisa Cervantes-Barragan</name>
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<name sortKey="Elliot, Ruth" sort="Elliot, Ruth" uniqKey="Elliot R" first="Ruth" last="Elliot">Ruth Elliot</name>
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<name sortKey="Karl, Nadja" sort="Karl, Nadja" uniqKey="Karl N" first="Nadja" last="Karl">Nadja Karl</name>
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<name sortKey="Gaughan, Christina" sort="Gaughan, Christina" uniqKey="Gaughan C" first="Christina" last="Gaughan">Christina Gaughan</name>
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<nlm:affiliation>Department of Cancer Biology, Lerner Research Institute, Cleveland, Ohio, United States of America.</nlm:affiliation>
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<name sortKey="Van Kuppeveld, Frank J M" sort="Van Kuppeveld, Frank J M" uniqKey="Van Kuppeveld F" first="Frank J M" last="Van Kuppeveld">Frank J M. Van Kuppeveld</name>
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<name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name>
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<name sortKey="Weiss, Susan R" sort="Weiss, Susan R" uniqKey="Weiss S" first="Susan R" last="Weiss">Susan R. Weiss</name>
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<nlm:affiliation>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.</nlm:affiliation>
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<name sortKey="Kalinke, Ulrich" sort="Kalinke, Ulrich" uniqKey="Kalinke U" first="Ulrich" last="Kalinke">Ulrich Kalinke</name>
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<name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name>
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<term>Animals</term>
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<term>Coronaviridae (immunology)</term>
<term>Coronavirus Infections (immunology)</term>
<term>Endonucleases (immunology)</term>
<term>Enzyme-Linked Immunosorbent Assay</term>
<term>Flow Cytometry</term>
<term>Host-Pathogen Interactions (immunology)</term>
<term>Humans</term>
<term>Immune Evasion (physiology)</term>
<term>Immunity, Innate (immunology)</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Real-Time Polymerase Chain Reaction</term>
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<term>Endonucleases</term>
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<term>Coronaviridae</term>
</keywords>
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<term>Coronaviridae</term>
<term>Coronavirus Infections</term>
<term>Host-Pathogen Interactions</term>
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<term>Immune Evasion</term>
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<term>Animals</term>
<term>Enzyme-Linked Immunosorbent Assay</term>
<term>Flow Cytometry</term>
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<term>Mice</term>
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<div type="abstract" xml:lang="en">Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.</div>
</front>
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<AbstractText>Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.</AbstractText>
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