Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response
- PMID: 22617958
- PMCID: PMC3377992
- DOI: 10.1038/msb.2012.17
Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response
Abstract
The cellular recognition of viruses evokes the secretion of type-I interferons (IFNs) that induce an antiviral protective state. By live-cell imaging, we show that key steps of virus-induced signal transduction, IFN-β expression, and induction of IFN-stimulated genes (ISGs) are stochastic events in individual cells. The heterogeneity in IFN production is of cellular-and not viral-origin, and temporal unpredictability of IFN-β expression is largely due to cell-intrinsic noise generated both upstream and downstream of the activation of nuclear factor-κB and IFN regulatory factor transcription factors. Subsequent ISG induction occurs as a stochastic all-or-nothing switch, where the responding cells are protected against virus replication. Mathematical modelling and experimental validation show that reliable antiviral protection in the face of multi-layered cellular stochasticity is achieved by paracrine response amplification. Achieving coherent responses through intercellular communication is likely to be a more widely used strategy by mammalian cells to cope with pervasive stochasticity in signalling and gene expression.
Conflict of interest statement
The authors declare that they have no conflict of interest.
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References
-
- Apostolou E, Thanos D (2008) Virus infection induces NF-κB-dependent interchromosomal associations mediating monoallelic IFN-β gene expression. Cell 134: 85–96 - PubMed
-
- Brennan K, Bowie AG (2010) Activation of host pattern recognition receptors by viruses. Curr Opin Microbiol 13: 503–507 - PubMed
-
- Brierley MM, Fish EN (2005) Stats: Multifaceted regulators of transcription. J Interferon Cytokine Res 25: 733–744 - PubMed
-
- Childs K, Stock N, Ross C, Andrejeva J, Hilton L, Skinner M, Randall R, Goodbourn S (2007) mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology 359: 190–200 - PubMed
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