Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: Coordinated dynamics emerging from cell-level noise

Roberto Bertolusso, Bing Tian, Yingxin Zhao, Leoncio Vergara, Aqeeb Sabree, Marta Iwanaszko, Tomasz Lipniacki, Allan R. Brasier, Marek Kimmel

Research output: Contribution to journalArticle

19 Citations (Scopus)

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-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.

Original languageEnglish (US)
Article numbere93396
JournalPLoS One
Volume9
Issue number4
DOIs
StatePublished - Apr 7 2014

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Double-Stranded RNA
double-stranded RNA
Innate Immunity
Noise
cells
Time series
time series analysis
Pattern Recognition Receptors
Gene Silencing
autoregulation
gene silencing
virus replication
Transcription Factors
Viruses
dose response
antagonists
Identification (control systems)
transcription factors
Messenger RNA
Genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation : Coordinated dynamics emerging from cell-level noise. / Bertolusso, Roberto; Tian, Bing; Zhao, Yingxin; Vergara, Leoncio; Sabree, Aqeeb; Iwanaszko, Marta; Lipniacki, Tomasz; Brasier, Allan R.; Kimmel, Marek.

In: PLoS One, Vol. 9, No. 4, e93396, 07.04.2014.

Research output: Contribution to journalArticle

Bertolusso, Roberto ; Tian, Bing ; Zhao, Yingxin ; Vergara, Leoncio ; Sabree, Aqeeb ; Iwanaszko, Marta ; Lipniacki, Tomasz ; Brasier, Allan R. ; Kimmel, Marek. / Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation : Coordinated dynamics emerging from cell-level noise. In: PLoS One. 2014 ; Vol. 9, No. 4.
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