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

Maciej Czerkies, Zbigniew Korwek, Wiktor Prus, Marek Kochańczyk, Joanna Jaruszewicz-Błońska, Karolina Tudelska, Sławomir Błoński, Marek Kimmel, Allan R. Brasier and Tomasz Lipniacki ()
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Maciej Czerkies: Polish Academy of Sciences
Zbigniew Korwek: Polish Academy of Sciences
Wiktor Prus: Polish Academy of Sciences
Marek Kochańczyk: Polish Academy of Sciences
Joanna Jaruszewicz-Błońska: Polish Academy of Sciences
Karolina Tudelska: Polish Academy of Sciences
Sławomir Błoński: Polish Academy of Sciences
Marek Kimmel: Rice University
Allan R. Brasier: University of Texas Medical Branch
Tomasz Lipniacki: Polish Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02640-8

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