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

Kai A Kropp, Kevin A Robertson, Garwin Sing, Sara Rodriguez-Martin, Mathieu Blanc, Paul Lacaze, Muhamad F B Noor Hassim, Mizanur R Khondoker, Andreas Busche, Paul Dickinson, Thorsten Forster, Birgit Strobl, Mathias Mueller, Stipan Jonjic, Ana Angulo, Peter Ghazal

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)10286-10299
Number of pages14
JournalJournal of Virology
Volume85
Issue number19
DOIs
Publication statusPublished - 2011

Keywords

  • Animals
  • Interferon Type I
  • Interferon-gamma
  • Macrophage Activation
  • Macrophages
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Muromegalovirus
  • Signal Transduction
  • Time Factors

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