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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Murine cytomegalovirus paralyzes macrophages by blocking IFN gamma-induced promoter assembly
Daniel L Popkin1, Mark A Watson, Elizabeth Karaskov
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
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.
Insights
Murine cytomegalovirus (MCMV) infection blocks interferon gamma (IFN-γ) gene regulation in macrophages by inhibiting transcription. This viral strategy paralyzes immune responses while allowing essential cellular functions to continue.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Macrophages are key immune cells activated by interferon gamma (IFN-γ).
- Human and murine cytomegaloviruses (CMV) infect macrophages, making IFN-γ-induced differentiation a target for viral evasion.
- CMVs benefit from blocking IFN-γ signaling to establish infection.
Purpose of the Study:
- To investigate how murine cytomegalovirus (MCMV) interferes with IFN-γ-induced gene regulation in macrophages.
- To determine the molecular mechanisms by which MCMV inhibits IFN-γ responses at the transcriptional level.
Main Methods:
- Analysis of gene expression in MCMV-infected macrophages treated with IFN-γ.
- Assessment of transcriptional regulation of IFN-γ-responsive promoters, including those dependent on IFN response factor 1 and class II transactivator.
- Distinguishing effects on chromosomal versus transiently transfected promoters.
Main Results:
- MCMV infection specifically inhibited IFN-γ-induced transcription of numerous genes in macrophages.
- The block occurred at the transcriptional level, independent of Janus kinase/signal transducer and activator of transcription pathway activation.
- MCMV did not affect basal transcription from IFN-γ-responsive promoters or most cellular transcripts.
- Viral inhibition was specific to chromosomal promoters, with MCMV blocking IFN-γ-induced promoter assembly.
Conclusions:
- MCMV employs a strategy to transcriptionally paralyze macrophages, specifically targeting IFN-γ-induced responses.
- The virus achieves this by disrupting the assembly of IFN-γ-responsive chromosomal promoters.
- This allows MCMV to evade immune detection and control while maintaining basal cellular functions.
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