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

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-?B 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-?B, a requirement for induction of IFN? expression. Autocrine IFN? initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-?B in first responder cells. Paracrine IFN?, 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.

SUBMITTER: Czerkies M 

PROVIDER: S-EPMC5799375 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature