Murine cytomegalovirus paralyzes macrophages by blocking IFN gamma-induced promoter assembly.
Macrophages (M phi) are activated by IFN gamma and are important cellular targets for infection by human and murine cytomegalovirus (MCMV), making it advantageous for CMVs to block IFN gamma-induced M phi differentiation. We found that MCMV infection inhibited IFN gamma regulation of many genes in M phi. MCMV infection blocked IFN gamma responses at the level of transcription without blocking Janus kinase/signal transducer and activator of transcription pathway activation and targeted IFN response factor 1- and class II transactivator-dependent and independent promoters. MCMV did not alter basal transcription from IFN gamma-responsive promoters and left the majority of cellular transcripts unchanged even after 48 h of infection. The effects of MCMV infection were specific to chromosomal rather than transiently transfected promoters. Characterization of the IFN gamma-responsive chromosomal class II transactivator promoter revealed that MCMV infection blocked IFN gamma-induced promoter assembly, allowing the virus to transcriptionally paralyze infected M phi responses while allowing basal transcription to proceed.
Popkin
Daniel L
DL
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Watson
Mark A
MA
Karaskov
Elizabeth
E
Dunn
Gavin P
GP
Bremner
Rod
R
Virgin
Herbert W
HW
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000821:virology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000472:pathogenicity*; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; C083728:MHC class II transactivator protein; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma