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 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.
Department of Statistics, Rice University, Houston, Texas, United States of America.
Roberto
R
Bertolusso
Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
Bing
B
Tian
Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America; Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, United States of America; Institute for Translational Sciences, UTMB, Galveston, Texas, United States of America.
Yingxin
Y
Zhao
Center for Biomedical Engineering, UTMB, Galveston, Texas, United States of America.
Leoncio
L
Vergara
Department of Statistics, Rice University, Houston, Texas, United States of America.
Aqeeb
A
Sabree
Systems Engineering Group, Silesian University of Technology, Gliwice, Poland.
Marta
M
Iwanaszko
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Tomasz
T
Lipniacki
Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America; Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, United States of America; Institute for Translational Sciences, UTMB, Galveston, Texas, United States of America.
Allan R
AR
Brasier
Department of Statistics, Rice University, Houston, Texas, United States of America; Systems Engineering Group, Silesian University of Technology, Gliwice, Poland.
Marek
M
Kimmel
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D018345:Mice, Knockout; D012330:RNA, Double-Stranded / Q000276:immunology / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3; D051996:Transcription Factor RelA; C512612:MAVS protein, mouse; C494232:IRF3 protein, human; C494233:Irf3 protein, mouse; C505371:MAVS protein, human; C498143:RELA protein, human; C498144:Rela protein, mouse; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse