Dynamic Cross Talk Model of the Epithelial Innate Immune Response to Double-Stranded RNA Stimulation: Coordinated Dynamics Emerging from Cell-Level Noise
dc.citation.firstpage | e93396 | en_US |
dc.citation.issueNumber | 4 | en_US |
dc.citation.journalTitle | PLoS ONE | en_US |
dc.citation.volumeNumber | 9 | en_US |
dc.contributor.author | Bertolusso, Roberto | en_US |
dc.contributor.author | Tian, Bing | en_US |
dc.contributor.author | Zhao, Yingxin | en_US |
dc.contributor.author | Vergara, Leoncio | en_US |
dc.contributor.author | Sabree, Aqeeb | en_US |
dc.contributor.author | Iwanaszko, Marta | en_US |
dc.contributor.author | Lipniacki, Tomasz | en_US |
dc.contributor.author | Brasier, Allan R. | en_US |
dc.contributor.author | Kimmel, Marek | en_US |
dc.date.accessioned | 2014-10-08T21:25:37Z | |
dc.date.available | 2014-10-08T21:25:37Z | |
dc.date.issued | 2014 | en_US |
dc.description.abstract | We 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.citation | Bertolusso, 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. | |
dc.identifier.doi | http://dx.doi.org/10.1371/journal.pone.0093396 | en_US |
dc.identifier.uri | https://hdl.handle.net/1911/77457 | |
dc.language.iso | eng | en_US |
dc.publisher | Public Library of Science | |
dc.rights | This 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.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Dynamic Cross Talk Model of the Epithelial Innate Immune Response to Double-Stranded RNA Stimulation: Coordinated Dynamics Emerging from Cell-Level Noise | en_US |
dc.type | Journal article | en_US |
dc.type.dcmi | Text | en_US |
dc.type.publication | publisher version | en_US |
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