Novel cell type-specific antiviral mechanism of interferon γ action in macrophages

Abstract

Interferon (IFN)-γ and macrophages (Mφ) play key roles in acute, persistent, and latent murine cytomegalovirus (MCMV) infection. IFN-γ mechanisms were compared in embryonic fibroblasts (MEFs) and bone marrow Mφ (BMMφ). IFN-γ inhibited MCMV replication in a signal transducer and activator of transcription (STAT)-1α-dependent manner much more effectively in BMMφ (∼100-fold) than MEF (5-10-fold). Although initial STAT-1α activation by IFN-γ was equivalent in MEF and BMMφ, microarray analysis demonstrated that IFN-γ regulates different sets of genes in BMMφ compared with MEFs. IFN-γ inhibition of MCMV growth was independent of known mechanisms involving IFN-γ/β, tumor necrosis factor α, inducible nitric oxide synthase, protein kinase RNA activated (PKR), RNaseL, and Mx1, and did not involve IFN-γ-induced soluble mediators. To characterize this novel mechanism, we identified the viral targets of IFN-γ action, which differed in MEF and BMMφ. In BMMφ, IFN-γ reduced immediate early 1 (IE1) mRNA during the first 3 h of infection, and significantly reduced IE1 protein expression for 96 h. Effects of IFN-γ on IE1 protein expression were independent of RNaseL and PKR. In contrast, - IFN-γ had no significant effects on IE1 protein or mRNA expression in MEFs, but did decrease late gene mRNA expression. These studies in primary cells define a novel mechanism of IFN-γ action restricted to Mφ, a cell type key for MCMV pathogenesis and latency.