Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages Journal Article

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Authors: Deng, X; Hackbart, M; Mettelman, R. C.; O'Brien, A; Mielech, A. M.; Yi, G; Kao, C. C.; Baker, S. C.
Article Title: Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages
Abstract: Coronaviruses are positive-sense RNA viruses that generate double-stranded RNA (dsRNA) intermediates during replication, yet evade detection by host innate immune sensors. Here we report that coronavirus nonstructural protein 15 (nsp15), an endoribonuclease, is required for evasion of dsRNA sensors. We evaluated two independent nsp15 mutant mouse coronaviruses, designated N15m1 and N15m3, and found that these viruses replicated poorly and induced rapid cell death in mouse bone marrow-derived macrophages. Infection of macrophages with N15m1, which expresses an unstable nsp15, or N15m3, which expresses a catalysis-deficient nsp15, activated MDA5, PKR, and the OAS/RNase L system, resulting in an early, robust induction of type I IFN, PKR-mediated apoptosis, and RNA degradation. Immunofluorescence imaging of nsp15 mutant virus-infected macrophages revealed significant dispersal of dsRNA early during infection, whereas in WT virus-infected cells, the majority of the dsRNA was associated with replication complexes. The loss of nsp15 activity also resulted in greatly attenuated disease in mice and stimulated a protective immune response. Taken together, our findings demonstrate that coronavirus nsp15 is critical for evasion of host dsRNA sensors in macrophages and reveal that modulating nsp15 stability and activity is a strategy for generating live-attenuated vaccines.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 114
Issue: 21
ISSN: 1091-6490; 0027-8424
Publisher: Unknown  
Journal Place: United States
Date Published: 2017
Start Page: E4251
End Page: E4260
Language: eng
DOI/URL:

10.1073/pnas.1618310114
Notes: LR: 20170524; JID: 7505876; OTO: NOTNLM; ppublish