2.50
Hdl Handle:
http://hdl.handle.net/10033/621007
Title:
Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.
Authors:
Kindler, Eveline; Gil-Cruz, Cristina; Spanier, Julia; Li, Yize; Wilhelm, Jochen; Rabouw, Huib H; Züst, Roland; Hwang, Mihyun; V'kovski, Philip; Stalder, Hanspeter; Marti, Sabrina; Habjan, Matthias; Cervantes-Barragan, Luisa; Elliot, Ruth; Karl, Nadja; Gaughan, Christina; van Kuppeveld, Frank J M; Silverman, Robert H; Keller, Markus; Ludewig, Burkhard; Bergmann, Cornelia C; Ziebuhr, John; Weiss, Susan R; Kalinke, Ulrich ( 0000-0003-0503-9564 ) ; Thiel, Volker
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.
Affiliation:
TWINCORE, Zentrum für experimentelle und klinische Infectionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Citation:
Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication. 2017, 13 (2):e1006195 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Feb-2017
URI:
http://hdl.handle.net/10033/621007
DOI:
10.1371/journal.ppat.1006195
PubMed ID:
28158275
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorKindler, Evelineen
dc.contributor.authorGil-Cruz, Cristinaen
dc.contributor.authorSpanier, Juliaen
dc.contributor.authorLi, Yizeen
dc.contributor.authorWilhelm, Jochenen
dc.contributor.authorRabouw, Huib Hen
dc.contributor.authorZüst, Rolanden
dc.contributor.authorHwang, Mihyunen
dc.contributor.authorV'kovski, Philipen
dc.contributor.authorStalder, Hanspeteren
dc.contributor.authorMarti, Sabrinaen
dc.contributor.authorHabjan, Matthiasen
dc.contributor.authorCervantes-Barragan, Luisaen
dc.contributor.authorElliot, Ruthen
dc.contributor.authorKarl, Nadjaen
dc.contributor.authorGaughan, Christinaen
dc.contributor.authorvan Kuppeveld, Frank J Men
dc.contributor.authorSilverman, Robert Hen
dc.contributor.authorKeller, Markusen
dc.contributor.authorLudewig, Burkharden
dc.contributor.authorBergmann, Cornelia Cen
dc.contributor.authorZiebuhr, Johnen
dc.contributor.authorWeiss, Susan Ren
dc.contributor.authorKalinke, Ulrichen
dc.contributor.authorThiel, Volkeren
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.en
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

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