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dc.contributor.authorKindler, Eveline
dc.contributor.authorGil-Cruz, Cristina
dc.contributor.authorSpanier, Julia
dc.contributor.authorLi, Yize
dc.contributor.authorWilhelm, Jochen
dc.contributor.authorRabouw, Huib H
dc.contributor.authorZüst, Roland
dc.contributor.authorHwang, Mihyun
dc.contributor.authorV'kovski, Philip
dc.contributor.authorStalder, Hanspeter
dc.contributor.authorMarti, Sabrina
dc.contributor.authorHabjan, Matthias
dc.contributor.authorCervantes-Barragan, Luisa
dc.contributor.authorElliot, Ruth
dc.contributor.authorKarl, Nadja
dc.contributor.authorGaughan, Christina
dc.contributor.authorvan Kuppeveld, Frank J M
dc.contributor.authorSilverman, Robert H
dc.contributor.authorKeller, Markus
dc.contributor.authorLudewig, Burkhard
dc.contributor.authorBergmann, Cornelia C
dc.contributor.authorZiebuhr, John
dc.contributor.authorWeiss, Susan R
dc.contributor.authorKalinke, Ulrich
dc.contributor.authorThiel, Volker
dc.date.accessioned2017-07-11T13:43:29Z
dc.date.available2017-07-11T13:43:29Z
dc.date.issued2017-02
dc.identifier.citationEarly endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication. 2017, 13 (2):e1006195 PLoS Pathog.en
dc.identifier.issn1553-7374
dc.identifier.pmid28158275
dc.identifier.doi10.1371/journal.ppat.1006195
dc.identifier.urihttp://hdl.handle.net/10033/621007
dc.description.abstractCoronaviruses 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.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshCoronaviridaeen
dc.subject.meshCoronavirus Infectionsen
dc.subject.meshEndonucleasesen
dc.subject.meshEnzyme-Linked Immunosorbent Assayen
dc.subject.meshFlow Cytometryen
dc.subject.meshHost-Pathogen Interactionsen
dc.subject.meshHumansen
dc.subject.meshImmune Evasionen
dc.subject.meshImmunity, Innateen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshReal-Time Polymerase Chain Reactionen
dc.subject.meshViral Proteinsen
dc.titleEarly endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.en
dc.typeArticleen
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infectionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.en
dc.identifier.journalPLoS pathogensen
refterms.dateFOA2018-06-13T21:21:55Z
html.description.abstractCoronaviruses 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.


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