Abstract
Murine gammaherpesvirus 68 (MHV-68) serves as a murine model for the human gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV). Like all herpesviruses, MHV-68 establishes latency with spontaneously recurring reactivation events. While it is known that type I interferon (IFN) is essential for survival of acute MHV-68 infection, its role during latency and reactivation is unclear. To define the contribution of the type I IFN system in control of MHV-68 acute infection and latency in vivo, we employed bioluminescent reporter mice (mx2-Luciferase and ifnb-Luciferase) to visualize IFN-b induction and type I IFN action. Splenocytes from latently infected wild type and inducible type I IFN receptor knockout (IFNARflox/flox) mice were adoptively transferred into wild type and IFNAR-deficient (IFNAR−/−) mice. Survival, virus burden and reporter gene induction was determined as a measure for the extent of in vivo reactivation. Our data show that (i) acute MHV-68 infection evokes an IFN response in vivo. (ii) MHV-68 latency is controlled by type I IFN signaling. (iii) An IFN response is induced upon MHV-68 reactivation in vivo. (iv) IFN controls the frequency of reactivation by acting on latently infected cells directly, thus suppressing reactivation. Overall, our findings demonstrate a substantial impact of the type I IFN system on the control of MHV-68 latency and upon its reactivation.
Published Version
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