title: Type I and type II interferons inhibit the translation of murine norovirus proteins.
abstract: Human noroviruses are responsible for more than 95% of nonbacterial epidemic gastroenteritis worldwide. Both onset and resolution of disease symptoms are rapid, suggesting that components of the innate immune response are critical in norovirus control. While the study of the human noroviruses has been hampered by the lack of small animal and tissue culture systems, our recent discovery of a murine norovirus (MNV) and its in vitro propagation have allowed us to begin addressing norovirus replication strategies and immune responses to norovirus infection. We have previously demonstrated that interferon responses are critical to control MNV-1 infection in vivo and to directly inhibit viral replication in vitro. We now extend these studies to define the molecular basis for interferon-mediated inhibition. Viral replication intermediates were not detected in permissive cells pretreated with type I interferon after either infection or transfection of virion-associated RNA, demonstrating a very early block to virion production that is after virus entry and uncoating. A similar absence of viral replication intermediates was observed in infected primary macrophages and dendritic cells pretreated with type I IFN. This was not due to degradation of incoming genomes in interferon-pretreated cells since similar levels of genomes were present in untreated and pretreated cells through 6 h of infection, and these genomes retained their integrity. Surprisingly, this block to the translation of viral proteins was not dependent on the well-characterized interferon-induced antiviral molecule PKR. Similar results were observed in cells pretreated with type II interferon, except that the inhibition of viral translation was dependent on PKR. Thus, both type I and type II interferon signaling inhibit norovirus translation in permissive myeloid cells, but they display distinct dependence on PKR for this inhibition.
authors.affiliation: Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Harish
authors.initials: H
authors.lastname: Changotra
authors.forename: Yali
authors.initials: Y
authors.lastname: Jia
authors.forename: Tara N
authors.initials: TN
authors.lastname: Moore
authors.forename: Guangliang
authors.initials: G
authors.lastname: Liu
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Kahan
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Sosnovtsev
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Karst
mesh_terms: D000818:Animals; D002460:Cell Line; D016679:Genome, Viral / Q000235:genetics; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D029322:Norovirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014771:Virion / Q000378:metabolism; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma; D019892:eIF-2 Kinase