Cell fate in antiviral response arises in the crosstalk of IRF, NF-κB and JAK/STAT pathways

Nat Commun. 2018 Feb 5;9(1):493. doi: 10.1038/s41467-017-02640-8.

Abstract

The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS. Poly(I:C) activates both IRF3 and NF-κB, a requirement for induction of IFNβ expression. Autocrine IFNβ initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-κB in first responder cells. Paracrine IFNβ, in turn, sensitises second responder cells through a JAK/STAT-mediated positive feedforward pathway that upregulates the positive-feedback components: RIG-I, PKR and OAS1A. In these sensitised cells, the 'live-or-die' decision phase following poly(I:C) exposure is shorter-they rapidly produce antiviral responses and commit to apoptosis. The interlinked positive feedback and feedforward signalling is key for coordinating cell fate decisions in cellular populations restricting pathogen spread.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',5'-Oligoadenylate Synthetase
  • Animals
  • Cell Line
  • DEAD Box Protein 58 / immunology
  • Feedback, Physiological
  • Gene Knockout Techniques
  • Immunity, Innate / drug effects
  • Immunity, Innate / immunology*
  • Interferon Inducers / pharmacology
  • Interferon Regulatory Factor-3 / drug effects
  • Interferon Regulatory Factor-3 / immunology*
  • Interferon-beta / immunology*
  • Janus Kinases / immunology*
  • Mice
  • NF-kappa B / drug effects
  • NF-kappa B / immunology*
  • Poly I-C / pharmacology
  • STAT Transcription Factors / immunology*
  • STAT1 Transcription Factor / genetics
  • Signal Transduction
  • Transcription Factor RelA / genetics
  • Up-Regulation
  • eIF-2 Kinase / immunology

Substances

  • Interferon Inducers
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • NF-kappa B
  • Rela protein, mouse
  • STAT Transcription Factors
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Transcription Factor RelA
  • Interferon-beta
  • Janus Kinases
  • eIF-2 Kinase
  • 2',5'-Oligoadenylate Synthetase
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • Poly I-C