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

PLoS Pathogens

Cornelia C. Bergmann¹  Susan R. Weiss¹  Hanspeter Stalder²  Eveline Kindler²  Luisa Cervantes-Barragan²  Nadja Karl²  Jochen Wilhelm³  Markus Keller³  Philip V’kovski⁴  Sabrina Marti⁵  Cristina Gil-Cruz⁵  Ruth Elliot⁵  Christina Gaughan⁵  Matthias Habjan⁶  Yize Li⁷  Burkhard Ludewig⁸  Julia Spanier⁹  Volker Thiel⁹  Ulrich Kalinke^1,10  Frank J. M. van Kuppeveld^1,11  Mihyun Hwang^1,12  Huib H. Rabouw^1,13  Roland Züst^1,14  John Ziebuhr^1,14  Robert H. Silverman^1,15 

[1] Department of Cancer Biology, Lerner Research Institute, Cleveland, Ohio, United States of America;Department of Infectious Diseases and Pathobiology, University of Bern, Bern, Switzerland;Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America;Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America;Federal Department of Home Affairs, Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland;Graduate School for Biomedical Science, University of Bern, Bern, Switzerland;Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany;Institute for Medical Virology, Justus-Liebig-University, Giessen, Germany;Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland;Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany;Max-Planck-Institute of Biochemistry, Martinsried, Germany;Singapore Immunology Network, Singapore;Universities Giessen & Marburg Lung Center (UGMLC), Deutsches Zentrum für Lungenforschung (DZL), Giessen, Germany;Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands;Washington University School of Medicine, St. Louis, MO, USA

关键词: Macrophages;    Viral replication;    Ribonucleases;    Coronaviruses;    RNA synthesis;    Host cells;    Ribosomal RNA;    L929 cells;   

DOI  :  10.1371/journal.ppat.1006195

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY