期刊
MOLECULAR SYSTEMS BIOLOGY
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/msb.2012.17
关键词
bacterial artificial chromosomes; gene expression; interferon regulatory factor-7; live-cell microscopy; multi-scale modelling
资金
- Georg-Christoph-Lichtenberg stipend
- federal state of Lower Saxony
- Helmholtz International Research School for Infection Biology
- German Research Foundation [SFB 900]
- BMBF MedSys
- BMBF ForSys initiative (ViroQuant)
- Helmholtz Association within Helmholtz Alliance on Systems Biology/SBCancer
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-beta 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-beta expression is largely due to cell-intrinsic noise generated both upstream and downstream of the activation of nuclear factor-kappa B 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. Molecular Systems Biology 8: 584; published online 22 May 2012; doi:10.1038/msb.2012.17
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