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Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response.
Rand, Ulfert Rinas, Melanie Schwerk, Johannes Nöhren, Gesa Linnes, Melanie Kröger, Andrea Flossdorf, Michael Kály-Kullai, Kristóf Hauser, Hansjörg Höfer, Thomas
Rand, Ulfert
Rinas, Melanie
Schwerk, Johannes
Nöhren, Gesa
Linnes, Melanie
Kröger, Andrea
Flossdorf, Michael
Kály-Kullai, Kristóf
Hauser, Hansjörg
Höfer, Thomas
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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.
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Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response. 2012, 8:584 Mol. Syst. Biol.
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en
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1744-4292
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Archived with thanks to Molecular systems biology