Dynamic Cross Talk Model of the Epithelial Innate Immune Response to Double-Stranded RNA Stimulation: Coordinated Dynamics Emerging from Cell-Level Noise

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dc.citation.firstpagee93396en_US
dc.citation.issueNumber4en_US
dc.citation.journalTitlePLoS ONEen_US
dc.citation.volumeNumber9en_US
dc.contributor.authorBertolusso, Robertoen_US
dc.contributor.authorTian, Bingen_US
dc.contributor.authorZhao, Yingxinen_US
dc.contributor.authorVergara, Leoncioen_US
dc.contributor.authorSabree, Aqeeben_US
dc.contributor.authorIwanaszko, Martaen_US
dc.contributor.authorLipniacki, Tomaszen_US
dc.contributor.authorBrasier, Allan R.en_US
dc.contributor.authorKimmel, Mareken_US
dc.date.accessioned2014-10-08T21:25:37Zen_US
dc.date.available2014-10-08T21:25:37Zen_US
dc.date.issued2014en_US
dc.description.abstractWe present an integrated dynamical cross-talk model of the epithelial innate immune reponse (IIR) incorporating RIG-I and TLR3 as the two major pattern recognition receptors (PRR) converging on the RelA and IRF3 transcriptional effectors. bioPN simulations reproduce biologically relevant gene-and protein abundance measurements in response to time course, gene silencing and dose-response perturbations both at the population and single cell level. Our computational predictions suggest that RelA and IRF3 are under auto- and cross-regulation. We predict, and confirm experimentally, that RIG-I mRNA expression is controlled by IRF7. We also predict the existence of a TLR3-dependent, IRF3-independent transcription factor (or factors) that control(s) expression of MAVS, IRF3 and members of the IKK family. Our model confirms the observed dsRNA dose-dependence of oscillatory patterns in single cells, with periods of 1-3 hr. Model fitting to time series, matched by knockdown data suggests that the NF-kB module operates in a different regime (with different coefficient values) than in the TNFa-stimulation experiments. In future studies, this model will serve as a foundation for identification of virus-encoded IIR antagonists and examination of stochastic effects of viral replication. Our model generates simulated time series, which reproduce the noisy oscillatory patterns of activity (with 1-3 hour period) observed in individual cells. Our work supports the hypothesis that the IIR is a phenomenon that emerged by evolution despite highly variable responses at an individual cell level.en_US
dc.identifier.citationBertolusso, Roberto, Tian, Bing, Zhao, Yingxin, et al.. "Dynamic Cross Talk Model of the Epithelial Innate Immune Response to Double-Stranded RNA Stimulation: Coordinated Dynamics Emerging from Cell-Level Noise." <i>PLoS ONE,</i> 9, no. 4 (2014) Public Library of Science: e93396. http://dx.doi.org/10.1371/journal.pone.0093396.en_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0093396en_US
dc.identifier.urihttps://hdl.handle.net/1911/77457en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleDynamic Cross Talk Model of the Epithelial Innate Immune Response to Double-Stranded RNA Stimulation: Coordinated Dynamics Emerging from Cell-Level Noiseen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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