Dataset Information

Philipson2015 - Innate immune response modulated by NLRX1

ABSTRACT: Casandra W. Philipson, Josep Bassaganya-Riera, Monica Viladomiu, Barbara Kronsteiner, Vida Abedi, Stefan Hoops, Pawel Michalak, Lin Kang, Stephen E. Girardin & Raquel Hontecillas. Modeling the Regulatory Mechanisms by Which NLRX1 Modulates Innate Immune Responses to Helicobacter pylori Infection. PLOS ONE 10, 9 (2015). 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.

SUBMITTER: Casandra Philipson

PROVIDER: BIOMD0000000596 | BioModels | 2024-09-02

REPOSITORIES: BioModels

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	BIOMD0000000596?filename=Philipson2015-biopax2.owl	Owl
	BIOMD0000000596?filename=Philipson2015-biopax3.owl	Owl
	BIOMD0000000596?filename=Philipson2015-matlab.m	Other
	BIOMD0000000596?filename=Philipson2015-octave.m	Other
	BIOMD0000000596?filename=Philipson2015.cps	Other

Items per page:

1 - 5 of 12

Publications

Modeling the Regulatory Mechanisms by Which NLRX1 Modulates Innate Immune Responses to Helicobacter pylori Infection.

Philipson Casandra W CW Bassaganya-Riera Josep J Viladomiu Monica M Kronsteiner Barbara B Abedi Vida V Hoops Stefan S Michalak Pawel P Kang Lin L Girardin Stephen E SE Hontecillas Raquel R

PloS one 20150914 9

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 infe ...[more]

PMID: 26367386

Similar Datasets

Project description:The model is first model of tissue level cellular immune responses to H. pylori in the publication, "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas. Abstract: Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

Project description:The model is the second model of the publication "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" published in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas. Abstract: Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

Project description:Leber2016 - Expanded model of Tfh-Tfr differentiation - Helicobacter pylori infection The parameters used in the model were obtained from experiments conducted by the authors, previous publications [ 1, 2, 3] and parameter optimisation carried out in the paper using particle swarm and genetic algorithms. This model is described in the article: Bistability analyses of CD4+ T follicular helper and regulatory cells during Helicobacter pylori infection. Leber A, Abedi V, Hontecillas R, Viladomiu M, Hoops S, Ciupe S, Caughman J, Andrew T, Bassaganya-Riera J. J. Theor. Biol. 2016 Jun; 398: 74-84 Abstract: T follicular helper (Tfh) cells are a highly plastic subset of CD4+ T cells specialized in providing B cell help and promoting inflammatory and effector responses during infectious and immune-mediate diseases. Helicobacter pylori is the dominant member of the gastric microbiota and exerts both beneficial and harmful effects on the host. Chronic inflammation in the context of H. pylori has been linked to an upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes, controlled in part by the cytokine, interleukin-21. This study investigates the differentiation and regulation of Tfh cells, major producers of IL-21, in the immune response to H. pylori challenge. To better understand the conditions influencing the promotion and inhibition of a chronically elevated Tfh population, we used top-down and bottom-up approaches to develop computational models of Tfh and T follicular regulatory (Tfr) cell differentiation. Stability analysis was used to characterize the presence of two bi-stable steady states in the calibrated Tfh/Tfr models. Stochastic simulation was used to illustrate the ability of the parameter set to dictate two distinct behavioral patterns. Furthermore, sensitivity analysis helped identify the importance of various parameters on the establishment of Tfh and Tfr cell populations. The core network model was expanded into a more comprehensive and predictive model by including cytokine production and signaling pathways. From the expanded network, the interaction between TGFB-Induced Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was displayed to exert control over the determination of the Tfh response. Model simulations predict that Tgif1 and RXR respectively induce and curtail Tfh responses. This computational hypothesis was validated experimentally by assaying Tgif1, RXR and Tfh in stomachs of mice infected with H. pylori. The impulse of RXR as shown in the paper (figure 7C) can be implemented by creating an event in the curated SBML file. This model is hosted on BioModels Database and identified by: BIOMD0000000625. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.