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Reversible inhibition of murine cytomegalovirus replication by gamma interferon (IFN- ) in primary macrophages involves a primed type I IFN-signaling subnetwork for full establishment of an immediate-early antiviral state

Kropp, K. A., Robertson, K. A., Sing, G., Rodriguez-Martin, S., Blanc, M., Lacaze, P., Hassim, M. F. B. N., Khondoker, M. R., Busche, A., Dickinson, P., Forster, T., Strobl, B., Mueller, M., Jonjic, S., Angulo, A. and Ghazal, Peter 2011. Reversible inhibition of murine cytomegalovirus replication by gamma interferon (IFN- ) in primary macrophages involves a primed type I IFN-signaling subnetwork for full establishment of an immediate-early antiviral state. Journal of Virology 85 (19) , pp. 10286-10299. 10.1128/JVI.00373-11

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: Supplemental material for this article may be found at http://dx.doi.org/10.1128/JVI.00373-11.
Publisher: American Society for Microbiology
ISSN: 0022-538X
Date of Acceptance: 20 July 2011
Last Modified: 21 Jun 2018 13:45
URI: http://orca.cf.ac.uk/id/eprint/112590

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