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.

Vaccinia Virus K1L and C7L Inhibit Antiviral Activities Induced by Type I Interferons

“…Overall, our data suggest that type I IFN can induce a PKR-independent pathway to block VACV protein translation and that this pathway can be inhibited by K1L and C7L. Interestingly, some recent studies with norovirus and picornavirus also suggest that a PKR-independent pathway is induced by type I IFN to inhibit protein translation in cells infected by these RNA viruses (8,20). Identification of the target for K1L and C7L may lead to the identification of a novel antiviral host factor/pathway that has broad antiviral effects.…”

Protruding Domain of Capsid Protein Is Necessary and Sufficient To Determine Murine Norovirus Replication and Pathogenesis In Vivo

“…The discovery of MNV, along with its capacity to grow in a smallanimal model, provides an opportunity to investigate NoV pathogenesis in vivo in greater detail. Previous studies have used the MNV model to identify and characterize viral and host determinants of MNV infection (3,10,13,18,31,38,42,58,63). Some of these studies reveal a profound role for STAT1-dependent host responses as a major determinant of MNV replication and dissemination in vivo, as well as pathology and mortality following MNV infection.…”

Targeting Norovirus: Strategies for the Discovery of New Antiviral Drugs

“…It was also demonstrated that IFN responses were critical to control MNV infection in vivo and inhibited viral replication in vitro (Karst et al, 2003;Wobus et al, 2004). Both type I and type II IFNs block the translation of viral proteins of MNV but while type II IFN-mediated inhibition is dependent on the well-characterized interferon-induced antiviral molecule PKR, type I IFNmediated inhibition occur through a PKR-independent process (Changotra et al, 2009). This data suggests that IFN may be a good therapeutic option for norovirus gastroenteritis.…”