| Murine cytomegalovirus (MCMV) provides an excellent small animal model for the species specific human pathogen human cytomegalovirus (HCMV). The primary disease pathology associated with HCMV infection in adults is due to reactivation from the latent state in the setting of immunocompromise. Despite its clinical importance, immune and viral mechanisms which regulate chronic infection, and particularly latency, have not been well defined. In this dissertation, I present experiments which analyzed the role of one important immune effector, interferon-γ (IFNγ), on regulation of MCMV infection.; IFNγ regulates all phases of MCMV infection: acute and chronic infection, latency and reactivation. Mice deficient in the IFNγ-receptor (IFNγR−/−) persistently shed virus in multiple organs even to 180 days post infection while congenic controls predominantly clear this productive infection. One consequence of this is the development and maintenance of arteritis. MCMV establishes latency in the bone marrow of IFNγR−/−, although bone marrow cultures reactivate at higher frequency. Addition of IFNγ blocks reactivation of MCMV from explanted spleen and lung from latently infected mice. This is due, in part, to inhibition of viral growth to detectable levels. These studies demonstrate that IFNγ regulates chronic MCMV infection in vivo, potentially by regulating reactivation from latency and subsequent growth from low level infection.; The mechanism of IFNγ's antiviral effects was examined in primary cultures of bone marrow derived macrophages (Mϕ) and murine embryonic fibroblasts (MEF). IFNγ inhibits MCMV replication in both cell types. MCMV is blocked in Mϕ at an immediate-early stage; in MEF, at a late stage. Cells derived from relevant knockout mice were used to show that IFNγ inhibition of MCMV growth in Mϕ is not due to PKR, RNAseL, Mx1; or soluble mediators, including NO, IFNαβ, or TNFα. Thus, IFNγ acts in a novel, cell type specific manner to inhibit MCMV replication.; A complete understanding of chronic MCMV infection and its regulation requires definition of the latent program. Through the use of representational difference analysis, three regions of the MCMV genome were identified as transcriptionally active in latently infected lung. This identification provides new information which should greatly enhance our understanding of MCMV chronic infection. |
