{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:37:11Z","timestamp":1781847431575,"version":"3.54.5"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,1,23]]},"abstract":"<jats:p>\n                    Type I interferons (IFNs) play an essential role in the host response to viral infection through the induction of numerous IFN-stimulated genes (ISGs), including important antiviral molecules such as PKR, RNase L, Mx, and iNOS. Yet, additional antiviral ISGs likely exist. IFN-stimulated gene 15 (ISG15) is a ubiquitin homolog that is rapidly up-regulated after viral infection, and it conjugates to a wide array of host proteins. Although it has been hypothesized that ISG15 functions as an antiviral molecule, the initial evaluation of ISG15-deficient mice revealed no defects in their responses to vesicular stomatitis virus or lymphocytic choriomeningitis virus, leaving open the important question of whether ISG15 is an antiviral molecule\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Here we demonstrate that ISG15 is critical for the host response to viral infection. ISG15\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice are more susceptible to influenza A\/WSN\/33 and influenza B\/Lee\/40 virus infections. ISG15\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice also exhibited increased susceptibility to both herpes simplex virus type 1 and murine gammaherpesvirus 68 infection and to Sindbis virus infection. The increased susceptibility of ISG15\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice to Sindbis virus infection was rescued by expressing wild-type ISG15, but not a mutant form of ISG15 that cannot form conjugates, from the Sindbis virus genome. The demonstration of ISG15 as a novel antiviral molecule with activity against both RNA and DNA viruses provides a target for the development of therapies against important human pathogens.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0607038104","type":"journal-article","created":{"date-parts":[[2007,1,16]],"date-time":"2007-01-16T22:18:23Z","timestamp":1168985903000},"page":"1371-1376","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":480,"title":["IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses"],"prefix":"10.1073","volume":"104","author":[{"given":"Deborah J.","family":"Lenschow","sequence":"first","affiliation":[{"name":"Departments of *Pathology and Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Lai","sequence":"additional","affiliation":[{"name":"Departments of *Pathology and 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Molekulare Leibniz Institute f\u00fcr Molekulare Pharmakologie, 13125 Berlin, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Levine","sequence":"additional","affiliation":[{"name":"**Departments of Internal Medicine and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Departments of *Pathology and Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Garc\u00eda-Sastre","sequence":"additional","affiliation":[{"name":"Department of Microbiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Leib","sequence":"additional","affiliation":[{"name":"Molecular Microbiology, and"},{"name":"Ophthalmology, Washington University School of Medicine, St. Louis, MO 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