title: Reversible inhibition of murine cytomegalovirus replication by gamma interferon (IFN-γ) in primary macrophages involves a primed type I IFN-signaling subnetwork for full establishment of an immediate-early antiviral state.
abstract: Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-α/β]) and type II interferon (IFN-γ) play a crucial role in activating macrophages and subsequently restricting viral infections. Both types of IFNs signal through related but distinct signaling pathways, inducing a vast number of interferon-stimulated genes that are overlapping but distinguishable. The exact mechanism by which IFNs, particularly IFN-γ, inhibit DNA viruses such as cytomegalovirus (CMV) is still not fully understood. Here, we investigate the antiviral state developed in macrophages upon reversible inhibition of murine CMV by IFN-γ. On the basis of molecular profiling of the reversible inhibition, we identify a significant contribution of a restricted type I IFN subnetwork linked with IFN-γ activation. Genetic knockout of the type I-signaling pathway, in the context of IFN-γ stimulation, revealed an essential requirement for a primed type I-signaling process in developing a full refractory state in macrophages. A minimal transient induction of IFN-β upon macrophage activation with IFN-γ is also detectable. In dose and kinetic viral replication inhibition experiments with IFN-γ, the establishment of an antiviral effect is demonstrated to occur within the first hours of infection. We show that the inhibitory mechanisms at these very early times involve a blockade of the viral major immediate-early promoter activity. Altogether our results show that a primed type I IFN subnetwork contributes to an immediate-early antiviral state induced by type II IFN activation of macrophages, with a potential further amplification loop contributed by transient induction of IFN-β.
authors.affiliation: Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, UK.
authors.forename: Kai A
authors.initials: KA
authors.lastname: Kropp
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Robertson
authors.forename: Garwin
authors.initials: G
authors.lastname: Sing
authors.forename: Sara
authors.initials: S
authors.lastname: Rodriguez-Martin
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blanc
authors.forename: Paul
authors.initials: P
authors.lastname: Lacaze
authors.forename: Muhamad F B Noor
authors.initials: MF
authors.lastname: Hassim
authors.forename: Mizanur R
authors.initials: MR
authors.lastname: Khondoker
authors.forename: Andreas
authors.initials: A
authors.lastname: Busche
authors.forename: Paul
authors.initials: P
authors.lastname: Dickinson
authors.forename: Thorsten
authors.initials: T
authors.lastname: Forster
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.forename: Mathias
authors.initials: M
authors.lastname: Mueller
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjic
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
mesh_terms: D000818:Animals; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000254:growth & development* / Q000276:immunology*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D007370:Interferon Type I; D007371:Interferon-gamma