Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response

Mol Syst Biol. 2012 May 22;8:584. doi: 10.1038/msb.2012.17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line / metabolism
  • Cell Line / virology
  • Chromosomes, Artificial, Bacterial
  • Gene Expression Regulation
  • Host-Pathogen Interactions
  • Interferon Type I / physiology*
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Mice
  • Models, Biological*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Newcastle disease virus / pathogenicity
  • Paracrine Communication*
  • Signal Transduction*
  • Single-Cell Analysis / methods*
  • Stochastic Processes*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Interferon Type I
  • NF-kappa B
  • Transcription Factors
  • Interferon-beta