Philipson2015 - Innate immune response modulated by NLRX1

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Related Publication
  • Modeling the Regulatory Mechanisms by Which NLRX1 Modulates Innate Immune Responses to Helicobacter pylori Infection.
  • Philipson CW, Bassaganya-Riera J, Viladomiu M, Kronsteiner B, Abedi V, Hoops S, Michalak P, Kang L, Girardin SE, Hontecillas R
  • PloS one , 1/ 2015 , Volume 10 , pages: e0137839
  • Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA, United States of America; Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA, United States of America.
  • Helicobacter pylori colonizes half of the world's population as the dominant member of the gastric microbiota resulting in a lifelong chronic infection. Host responses toward the bacterium can result in asymptomatic, pathogenic or even favorable health outcomes; however, mechanisms underlying the dual role of H. pylori as a commensal versus pathogenic organism are not well characterized. Recent evidence suggests mononuclear phagocytes are largely involved in shaping dominant immunity during infection mediating the balance between host tolerance and succumbing to overt disease. We combined computational modeling, bioinformatics and experimental validation in order to investigate interactions between macrophages and intracellular H. pylori. Global transcriptomic analysis on bone marrow-derived macrophages (BMDM) in a gentamycin protection assay at six time points unveiled the presence of three sequential host response waves: an early transient regulatory gene module followed by sustained and late effector responses. Kinetic behaviors of pattern recognition receptors (PRRs) are linked to differential expression of spatiotemporal response waves and function to induce effector immunity through extracellular and intracellular detection of H. pylori. We report that bacterial interaction with the host intracellular environment caused significant suppression of regulatory NLRC3 and NLRX1 in a pattern inverse to early regulatory responses. To further delineate complex immune responses and pathway crosstalk between effector and regulatory PRRs, we built a computational model calibrated using time-series RNAseq data. Our validated computational hypotheses are that: 1) NLRX1 expression regulates bacterial burden in macrophages; and 2) early host response cytokines down-regulate NLRX1 expression through a negative feedback circuit. This paper applies modeling approaches to characterize the regulatory role of NLRX1 in mechanisms of host tolerance employed by macrophages to respond to and/or to co-exist with intracellular H. pylori.
Ashley Xavier, Casandra Philipson

Metadata information

BioModels Database BIOMD0000000596
BioModels Database MODEL1508180000
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Model files

BIOMD0000000596_url.xml SBML L2V4 representation of Philipson2015 - Innate immune response modulated by NLRX1 178.82 KB Preview | Download

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BIOMD0000000596-biopax2.owl Auto-generated BioPAX (Level 2) 31.81 KB Preview | Download
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  • Model originally submitted by : Casandra Philipson
  • Submitted: Aug 18, 2015 6:01:04 PM
  • Last Modified: Nov 1, 2018 10:18:32 AM
  • Version: 4 public model Download this version
    • Submitted on: Nov 1, 2018 10:18:32 AM
    • Submitted by: Ashley Xavier
    • With comment: Automatically added model identifier BIOMD0000000596
  • Version: 2 public model Download this version
    • Submitted on: Mar 30, 2016 4:13:34 PM
    • Submitted by: Casandra Philipson
    • With comment: Current version of Philipson2015 - Innate immune response modulated by NLRX1
  • Version: 1 public model Download this version
    • Submitted on: Aug 18, 2015 6:01:04 PM
    • Submitted by: Casandra Philipson
    • With comment: Original import of NLRX1 Modeling
Curator's comment:
(added: 30 Mar 2016, 15:46:22, updated: 30 Mar 2016, 15:46:22)
The model reproduces the wildtype condition, i.e. figure 3E of the reference publication. The model is not opening in any other tools (tried with CellDesigner, SimBiology, DEDiscover, SBMLodeSolver) except for Copasi as it has SBML layout package. So, the simulation result has been tested using Copasi v4.16 (Build 104)(the paper has also used Copasi for simulation).