title: Essential cell-autonomous role for interferon (IFN) regulatory factor 1 in IFN-γ-mediated inhibition of norovirus replication in macrophages.
abstract: Noroviruses (NVs) cause the majority of cases of epidemic nonbacterial gastroenteritis worldwide and contribute to endemic enteric disease. However, the molecular mechanisms responsible for immune control of their replication are not completely understood. Here we report that the transcription factor interferon regulatory factor 1 (IRF-1) is required for control of murine NV (MNV) replication and pathogenesis in vivo. This led us to studies documenting a cell-autonomous role for IRF-1 in gamma interferon (IFN-γ)-mediated inhibition of MNV replication in primary macrophages. This role of IRF-1 in the inhibition of MNV replication by IFN-γ is independent of IFN-αβ signaling. While the signal transducer and activator of transcription STAT-1 was also required for IFN-γ-mediated inhibition of MNV replication in vitro, class II transactivator (CIITA), interferon regulatory factor 3 (IRF-3), and interferon regulatory factor 7 (IRF-7) were not required. We therefore hypothesized that there must be a subset of IFN-stimulated genes (ISGs) regulated by IFN-γ in a manner dependent only on STAT-1 and IRF-1. Analysis of transcriptional profiles of macrophages lacking various transcription factors confirmed this hypothesis. These studies identify a key role for IRF-1 in IFN-γ-dependent control of norovirus infection in mice and macrophages.
authors.affiliation: Department of Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Maloney
authors.forename: Larissa B
authors.initials: LB
authors.lastname: Thackray
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.forename: Seungmin
authors.initials: S
authors.lastname: Hwang
authors.forename: Erning
authors.initials: E
authors.lastname: Duan
authors.forename: Punit
authors.initials: P
authors.lastname: Vachharajani
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D005759:Gastroenteritis / Q000821:virology*; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D029322:Norovirus / Q000502:physiology*; D012372:ROC Curve; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018709:Statistics, Nonparametric; D059467:Transcriptome; D014779:Virus Replication / Q000502:physiology*
chemical_list: D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma