title: ISG15 functions as an interferon-mediated antiviral effector early in the murine norovirus life cycle.
abstract: Human noroviruses (HuNoV) are the leading cause of nonbacterial gastroenteritis worldwide. Similar to HuNoV, murine noroviruses (MNV) are enteric pathogens spread via the fecal-oral route and have been isolated from numerous mouse facilities worldwide. Type I and type II interferons (IFN) restrict MNV-1 replication; however, the antiviral effectors impacting MNV-1 downstream of IFN signaling are largely unknown. Studies using dendritic cells, macrophages, and mice deficient in free and conjugated forms of interferon-stimulated gene 15 (ISG15) revealed that ISG15 conjugation contributes to protection against MNV-1 both in vitro and in vivo. ISG15 inhibited a step early in the viral life cycle upstream of viral genome transcription. Directly transfecting MNV-1 RNA into IFN-stimulated mouse embryonic fibroblasts (MEFs) and bone marrow-derived dendritic cells (BMDC) lacking ISG15 conjugates bypassed the antiviral activity of ISG15, further suggesting that ISG15 conjugates restrict the MNV-1 life cycle at the viral entry/uncoating step. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of early stages of MNV-1 replication.
  
  
  OBJECTIVE
  Type I IFNs are important in controlling murine norovirus 1 (MNV-1) infections; however, the proteins induced by IFNs that restrict viral growth are largely unknown. This report reveals that interferon-stimulated gene 15 (ISG15) mitigates MNV-1 replication both in vitro and in vivo. In addition, it shows that ISG15 inhibits MNV-1 replication by targeting an early step in the viral life cycle, MNV-1 entry and/or uncoating. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of viral entry/uncoating.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Marisela R
authors.initials: MR
authors.lastname: Rodriguez
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Monte
authors.affiliation: Department of Infectious Disease, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Larissa B
authors.initials: LB
authors.lastname: Thackray
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Infectious Disease, Washington University School of Medicine, St. Louis, Missouri, USA dlenscho@dom.wustl.edu.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lenschow
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D016679:Genome, Viral / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D008018:Life Cycle Stages / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D029322:Norovirus / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D014452:Ubiquitins