Original Article

Novel Cell Type–specific Antiviral Mechanism of Interferon Action in Macrophages

Correspondence to: Herbert W. Virgin, IV, Dept. of Pathology and Immunology and Dept. of Molecular Microbiology, Washington University School of Medicine, Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Tel:314-362-9223 Fax:314-362-4096 E-mail:virgin{at}immunology.wustl.edu.

Interferon (IFN)- and macrophages (M) play key roles in acute, persistent, and latent murine cytomegalovirus (MCMV) infection. IFN- mechanisms were compared in embryonic fibroblasts (MEFs) and bone marrow M (BMM). IFN- inhibited MCMV replication in a signal transducer and activator of transcription (STAT)-1–dependent manner much more effectively in BMM (100-fold) than MEF (5–10-fold). Although initial STAT-1 activation by IFN- was equivalent in MEF and BMM, microarray analysis demonstrated that IFN- regulates different sets of genes in BMM compared with MEFs. IFN- inhibition of MCMV growth was independent of known mechanisms involving IFN-/ß, tumor necrosis factor , inducible nitric oxide synthase, protein kinase RNA activated (PKR), RNaseL, and Mx1, and did not involve IFN-–induced soluble mediators. To characterize this novel mechanism, we identified the viral targets of IFN- action, which differed in MEF and BMM. In BMM, IFN- 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- on IE1 protein expression were independent of RNaseL and PKR. In contrast, IFN- 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- action restricted to M, a cell type key for MCMV pathogenesis and latency.

Key Words: interferon , cytomegalovirus, signal transducer and activator of transcription 1, microarray analysis, macrophage

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