Mouse gammaherpesvirus-68 infection acts as a rheostat to set the level of type I interferon signaling in primary macrophages.

Type I interferon (IFN) is a critical antiviral response of the host. We found that Interferon Regulatory Factor 3 (IRF-3) was responsible for induction of type I IFN following mouse gammaherpesvirus-68 (MHV68) infection of primary macrophages. Intriguingly, type I IFN signaling was maintained throughout the entire MHV68 replication cycle, in spite of several known viral IFN antagonists. However, MHV68-infected primary macrophages displayed attenuated responses to exogenous type I IFN, suggesting that MHV68 controls the level of type I IFN signaling that is allowed to occur during replication. Type I IFN receptor and IRF-3 were necessary to attenuate transcription of MHV68 RTA, an immediate early gene critical for replication. Furthermore, higher constitutive activity of RTA promoters was observed in the absence of type I IFN signaling. Our study suggests that MHV68 has preserved the ability to sense type I IFN status of the host in order to limit lytic replication.

Coordinate regulation of DNA damage and type I interferon responses imposes an antiviral state that attenuates mouse gammaherpesvirus type 68 replication in primary macrophages.

DNA damage response (DDR) is a sophisticated cellular network that detects and repairs DNA breaks. Viruses are known to activate the DDR and usurp certain DDR components to facilitate replication. Intriguingly, viruses also inhibit several DDR proteins, suggesting that this cellular network has both proviral and antiviral features, with the nature of the latter still poorly understood. In this study we show that irradiation of primary murine macrophages was associated with enhanced expression of several antiviral interferon (IFN)-stimulated genes (ISGs). ISG induction in irradiated macrophages was dependent on type I IFN signaling, a functional DNA damage sensor complex, and ataxia-telangiectasia mutated kinase. Furthermore, IFN regulatory factor 1 was also required for the optimal expression of antiviral ISGs in irradiated macrophages. Importantly, DDR-mediated activation of type I IFN signaling contributed to increased resistance to mouse gammaherpesvirus 68 replication, suggesting that the coordinate regulation of DDR and type I IFN signaling may have evolved as a component of the innate immune response to virus infections.