{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:48:51Z","timestamp":1790743731066,"version":"4.1.0"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T00:00:00Z","timestamp":1488326400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI114920"],"award-info":[{"award-number":["R21AI114920"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI104887"],"award-info":[{"award-number":["R01AI104887"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["F32AI114143"],"award-info":[{"award-number":["F32AI114143"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Viruses in the family<jats:named-content content-type=\"genus-species\">Coronaviridae<\/jats:named-content>, within the order<jats:named-content content-type=\"genus-species\">Nidovirales<\/jats:named-content>, are etiologic agents of a range of human and animal diseases, including both mild and severe respiratory diseases in humans. These viruses encode conserved replicase and structural proteins as well as more diverse accessory proteins, encoded in the 3\u2032 ends of their genomes, that often act as host cell antagonists. We previously showed that 2\u2032,5\u2032-phosphodiesterases (2\u2032,5\u2032-PDEs) encoded by the prototypical<jats:named-content content-type=\"genus-species\">Betacoronavirus<\/jats:named-content>, mouse hepatitis virus (MHV), and by Middle East respiratory syndrome-associated coronavirus antagonize the oligoadenylate-RNase L (OAS-RNase L) pathway. Here we report that additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses infecting both humans and animals, encode 2\u2032,5\u2032-PDEs capable of antagonizing RNase L. We used a chimeric MHV system (MHV<jats:sup>Mut<\/jats:sup>) in which exogenous PDEs were expressed from an MHV backbone lacking the gene for a functional NS2 protein, the endogenous RNase L antagonist. With this system, we found that 2\u2032,5\u2032-PDEs encoded by the human coronavirus HCoV-OC43 (OC43; an agent of the common cold), human enteric coronavirus (HECoV), equine coronavirus (ECoV), and equine torovirus Berne (BEV) are enzymatically active, rescue replication of MHV<jats:sup>Mut<\/jats:sup>in bone marrow-derived macrophages, and inhibit RNase L-mediated rRNA degradation in these cells. Additionally, PDEs encoded by OC43 and BEV rescue MHV<jats:sup>Mut<\/jats:sup>replication and restore pathogenesis in wild-type (WT) B6 mice. This finding expands the range of viruses known to encode antagonists of the potent OAS-RNase L antiviral pathway, highlighting its importance in a range of species as well as the selective pressures exerted on viruses to antagonize it.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Viruses in the family<jats:named-content content-type=\"genus-species\">Coronaviridae<\/jats:named-content>include important human and animal pathogens, including the recently emerged viruses severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome-associated coronavirus (MERS-CoV). We showed previously that two viruses within the genus<jats:named-content content-type=\"genus-species\">Betacoronavirus<\/jats:named-content>, mouse hepatitis virus (MHV) and MERS-CoV, encode 2\u2032,5\u2032-phosphodiesterases (2\u2032,5\u2032-PDEs) that antagonize the OAS-RNase L pathway, and we report here that these proteins are furthermore conserved among additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses, suggesting that they may play critical roles in pathogenesis. As there are no licensed vaccines or effective antivirals against human coronaviruses and few against those infecting animals, identifying viral proteins contributing to virulence can inform therapeutic development. Thus, this work demonstrates that a potent antagonist of host antiviral defenses is encoded by multiple and diverse viruses within the family<jats:named-content content-type=\"genus-species\">Coronaviridae<\/jats:named-content>, presenting a possible broad-spectrum therapeutic target.<\/jats:p>","DOI":"10.1128\/jvi.02201-16","type":"journal-article","created":{"date-parts":[[2016,12,22]],"date-time":"2016-12-22T02:27:36Z","timestamp":1482373656000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":45,"title":["Lineage A Betacoronavirus NS2 Proteins and the Homologous Torovirus Berne pp1a Carboxy-Terminal Domain Are Phosphodiesterases That Antagonize Activation of RNase L"],"prefix":"10.1128","volume":"91","author":[{"given":"Stephen A.","family":"Goldstein","sequence":"first","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M.","family":"Thornbrough","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7660-5255","authenticated-orcid":false,"given":"Babal K.","family":"Jha","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yize","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Quiroz-Figueroa","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie I.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-4528","authenticated-orcid":false,"given":"Susan R.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-385885-6.00009-2"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(03)00865-9"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkf645"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.04.011"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01471-07"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00258-16"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01312-14"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1306917110"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00701-15"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.11.037"},{"key":"e_1_3_2_12_2","first-page":"103","article-title":"A convenient and sensitive fluorescence resonance energy transfer assay for RNase L and 2\u2032,5\u2032 oligoadenylates","volume":"116","author":"Thakur CS","year":"2005","unstructured":"Thakur CS Xu Z Wang Z Novince Z Silverman RH . 2005. 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