title: Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response.
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.
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Ulfert
authors.initials: U
authors.lastname: Rand
authors.forename: Melanie
authors.initials: M
authors.lastname: Rinas
authors.forename: Johannes
authors.initials: J
authors.lastname: Schwerk
authors.forename: Gesa
authors.initials: G
authors.lastname: Nöhren
authors.forename: Melanie
authors.initials: M
authors.lastname: Linnes
authors.forename: Andrea
authors.initials: A
authors.lastname: Kröger
authors.forename: Michael
authors.initials: M
authors.lastname: Flossdorf
authors.forename: Kristóf
authors.initials: K
authors.lastname: Kály-Kullai
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Hauser
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.forename: Mario
authors.initials: M
authors.lastname: Köster
mesh_terms: D000818:Animals; D002460:Cell Line / Q000378:metabolism / Q000821:virology; D022202:Chromosomes, Artificial, Bacterial; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D007370:Interferon Type I / Q000502:physiology*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009522:Newcastle disease virus / Q000472:pathogenicity; D019899:Paracrine Communication; D015398:Signal Transduction; D059010:Single-Cell Analysis / Q000379:methods*; D013269:Stochastic Processes; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D016328:NF-kappa B; D014157:Transcription Factors; D016899:Interferon-beta