Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise.
We present an integrated dynamical cross-talk model of the epithelial innate immune response (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 p...
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doaj-e207d84aaa0f41919778d7f3225b8a092020-11-25T01:17:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0194e9339610.1371/journal.pone.0093396Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise.Roberto BertolussoBing TianYingxin ZhaoLeoncio VergaraAqeeb SabreeMarta IwanaszkoTomasz LipniackiAllan R BrasierMarek KimmelWe present an integrated dynamical cross-talk model of the epithelial innate immune response (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-κB module operates in a different regime (with different coefficient values) than in the TNFα-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.http://europepmc.org/articles/PMC3977818?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Roberto Bertolusso Bing Tian Yingxin Zhao Leoncio Vergara Aqeeb Sabree Marta Iwanaszko Tomasz Lipniacki Allan R Brasier Marek Kimmel |
spellingShingle |
Roberto Bertolusso Bing Tian Yingxin Zhao Leoncio Vergara Aqeeb Sabree Marta Iwanaszko Tomasz Lipniacki Allan R Brasier Marek Kimmel Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. PLoS ONE |
author_facet |
Roberto Bertolusso Bing Tian Yingxin Zhao Leoncio Vergara Aqeeb Sabree Marta Iwanaszko Tomasz Lipniacki Allan R Brasier Marek Kimmel |
author_sort |
Roberto Bertolusso |
title |
Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. |
title_short |
Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. |
title_full |
Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. |
title_fullStr |
Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. |
title_full_unstemmed |
Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. |
title_sort |
dynamic cross talk model of the epithelial innate immune response to double-stranded rna stimulation: coordinated dynamics emerging from cell-level noise. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
We present an integrated dynamical cross-talk model of the epithelial innate immune response (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-κB module operates in a different regime (with different coefficient values) than in the TNFα-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. |
url |
http://europepmc.org/articles/PMC3977818?pdf=render |
work_keys_str_mv |
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