title: Stochastic expression of the interferon-β gene.
abstract: Virus infection of mammalian cells induces the production of high levels of type I interferons (IFNα and β), cytokines that orchestrate antiviral innate and adaptive immunity. Previous studies have shown that only a fraction of the infected cells produce IFN. However, the mechanisms responsible for this stochastic expression are poorly understood. Here we report an in depth analysis of IFN-expressing and non-expressing mouse cells infected with Sendai virus. Mouse embryonic fibroblasts in which an internal ribosome entry site/yellow fluorescent protein gene was inserted downstream from the endogenous IFNβ gene were used to distinguish between the two cell types, and they were isolated from each other using fluorescence-activated cell sorting methods. Analysis of the separated cells revealed that stochastic IFNβ expression is a consequence of cell-to-cell variability in the levels and/or activities of limiting components at every level of the virus induction process, ranging from viral replication and expression, to the sensing of viral RNA by host factors, to activation of the signaling pathway, to the levels of activated transcription factors. We propose that this highly complex stochastic IFNβ gene expression evolved to optimize both the level and distribution of type I IFNs in response to virus infection.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Zhao
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Hemali
authors.initials: H
authors.lastname: Phatnani
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000276:immunology* / Q000821:virology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000235:genetics; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D029082:Sendai virus / Q000254:growth & development / Q000276:immunology*; D015398:Signal Transduction; D013269:Stochastic Processes; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic; D014779:Virus Replication; D000097905:Roundabout Proteins
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011070:Poly I-C; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins