{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T23:25:20Z","timestamp":1773098720121,"version":"3.50.1"},"reference-count":59,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T00:00:00Z","timestamp":1401580800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Coronaviruses express a deubiquitinating protein, the papain-like protease-2 (PLP2), that removes both ubiquitin and the ubiquitin-like interferon (IFN)-stimulated gene 15 (ISG15) protein from target proteins. ISG15 has antiviral activity against a number of viruses; therefore, we examined the effect of ISG15 conjugation (ISGylation) in a model of acute viral hepatitis induced by the murine hepatitis virus strain 3 (MHV-3) coronavirus. Mice deficient in the ISG15 deconjugating enzyme, ubiquitin-specific peptidase-18 (USP18), accumulate high levels of ISG15-conjugated proteins and are hypersensitive to type I IFN. Infecting USP18\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice with MHV-3 resulted in extended survival (8 \u00b1 1.2 versus 4 days) and in improved liver histology, a decreased inflammatory response, and viral titers 1 to 2 logs lower than in USP18\n            <jats:sup>+\/+<\/jats:sup>\n            mice. The suppression of viral replication was not due to increased IFN since infected USP18\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice had neither increased hepatic IFN-\u03b1, -\u03b2, or -\u03b3 mRNA nor circulating protein. Instead, delayed MHV-3 replication coincided with high levels of cellular ISGylation. Decreasing ISGylation by knockdown of the ISG15 E1 enzyme, Ube1L, in primary USP18\n            <jats:sup>+\/+<\/jats:sup>\n            and USP18\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            hepatocytes led to increased MHV-3 replication. Both\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            , increasing MHV-3 titers were coincident with increased PLP2 mRNA and decreased ISGylation over the course of infection. The pharmacologic inhibition of the PLP2 enzyme\n            <jats:italic>in vitro<\/jats:italic>\n            led to decreased MHV-3 replication. Overall, these results demonstrate the antiviral effect of ISGylation in an\n            <jats:italic>in vivo<\/jats:italic>\n            model of coronavirus-induced mouse hepatitis and illustrate that PLP2 manipulates the host innate immune response through the ISG15\/USP18 pathway.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            There have been a number of serious worldwide pandemics due to widespread infections by coronavirus. This virus (in its many forms) is difficult to treat, in part because it is very good at finding \u201choles\u201d in the way that the host (the infected individual) tries to control and eliminate the virus. In this study, we demonstrate that an important host viral defense\u2014the ISG15 pathway\u2014is only partially effective in controlling severe coronavirus infection. Activation of the pathway is very good at suppressing viral production, but over time the virus overwhelms the host response and the effects of the ISG15 pathway. These data provide insight into host-virus interactions during coronavirus infection and suggest that the ISG15 pathway is a reasonable target for controlling severe coronavirus infection although the best treatment will likely involve multiple pathways and targets.\n          <\/jats:p>","DOI":"10.1128\/jvi.03801-13","type":"journal-article","created":{"date-parts":[[2014,3,20]],"date-time":"2014-03-20T03:49:55Z","timestamp":1395287395000},"page":"6195-6204","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":19,"title":["Protein Interferon-Stimulated Gene 15 Conjugation Delays but Does Not Overcome Coronavirus Proliferation in a Model of Fulminant Hepatitis"],"prefix":"10.1128","volume":"88","author":[{"given":"Xue-Zhong","family":"Ma","sequence":"first","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agata","family":"Bartczak","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itay","family":"Shalev","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Smil","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limin","family":"Chen","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jim","family":"Phillips","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan J.","family":"Feld","sequence":"additional","affiliation":[{"name":"Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, University of Toronto, Toronto, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazia","family":"Selzner","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Levy","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"McGilvray","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1085952"},{"key":"e_1_3_2_3_2","volume-title":"Summary table of SARS cases by country, 1 November 2002\u20137 August 2003","author":"World Health Organization","year":"2003","unstructured":"World Health Organization. 15 Aug 2003, posting date. Summary table of SARS cases by country, 1 November 2002\u20137 August 2003. WHO, Geneva, Switzerland. http:\/\/www.who.int\/csr\/sars\/country\/2003_08_15\/en\/."},{"key":"e_1_3_2_4_2","volume-title":"Novel coronavirus infection-update","author":"World Health Organization","year":"2013","unstructured":"World Health Organization. 16 Feb 2013, posting date. Novel coronavirus infection-update. World Health Organization, Geneva, Switzerland. http:\/\/www.who.int\/csr\/don\/2013_02_16\/en\/."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1732"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1343"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.154.4.1150"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200318114"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.69.9.5252-5260.1995"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.48.32222"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/279523a0"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/v2102154"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.08.132"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504754102"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208435200"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.15.6338-6345.2005"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2009.23"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.08.038"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109078200"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1010202"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1133"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1056303"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601149"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-8-95"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.015388-0"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.10.046"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.01.059"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.01.028"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01219-10"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.24.15189-15198.2005"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2007.07.006"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.05.033"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00058457"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00747-06"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805240105"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.3.362"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.002"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1521607"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909144107"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01667-08"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2010.11.003"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01466-09"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.22.13974-13983.2005"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607038104"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000096"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2009.195545"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01590-08"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01512-06"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2007.01.020"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030802"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.4.2079-2086.2005"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02406-09"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704870200"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115843"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101609"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.3390\/v1030689"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00317-09"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.24.15199-15208.2005"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510851103"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02747-06"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.03801-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.03801-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T15:38:54Z","timestamp":1646494734000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.03801-13"}},"subtitle":[],"editor":[{"given":"S.","family":"Perlman","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2014,6]]},"references-count":59,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2014,6]]}},"alternative-id":["10.1128\/JVI.03801-13"],"URL":"https:\/\/doi.org\/10.1128\/jvi.03801-13","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6]]},"assertion":[{"value":"2014-01-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-03-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-05-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}