A mathematical model of CR3/TLR2 crosstalk in the context of Francisella tularensis infection

Complement Receptor 3 (CR3) and Toll-like Receptor 2 (TLR2) are pattern recognition receptors expressed on the surface of human macrophages. Although these receptors are essential components for recognition by the innate immune system, pathogen coordinated crosstalk between them can suppress the pro...

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Bibliographic Details
Published in:PLoS computational biology 2012-11, Vol.8 (11), p.e1002757-e1002757
Main Authors: Leander, Rachel, Dai, Shipan, Schlesinger, Larry S, Friedman, Avner
Format: Article
Language:English
Subjects:
Bacteria
Bacterial infections
Biology
Computer Science
Computer Simulation
Development and progression
Experiments
Feedback
Francisella tularensis
Francisella tularensis - metabolism
Health aspects
Host-Pathogen Interactions - immunology
Host-Pathogen Interactions - physiology
Humans
Hypotheses
Infections
Kinases
Ligands
Macrophage-1 Antigen - metabolism
Macrophages - metabolism
Macrophages - microbiology
Mathematical models
Medicine
Models, Biological
Pattern recognition
Phagocytosis - physiology
Phosphorylation
Physiological aspects
Proteins
Signal Transduction - physiology
Toll-Like Receptor 2 - metabolism
Toll-like receptors
Tularemia - immunology
Tularemia - metabolism
Tularemia - microbiology
Virulence (Microbiology)
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Summary:Complement Receptor 3 (CR3) and Toll-like Receptor 2 (TLR2) are pattern recognition receptors expressed on the surface of human macrophages. Although these receptors are essential components for recognition by the innate immune system, pathogen coordinated crosstalk between them can suppress the production of protective cytokines and promote infection. Recognition of the virulent Schu S4 strain of the intracellular pathogen Francisella tularensis by host macrophages involves CR3/TLR2 crosstalk. Although experimental data provide evidence that Lyn kinase and PI3K are essential components of the CR3 pathway that influences TLR2 activity, additional responsible upstream signaling components remain unknown. In this paper we construct a mathematical model of CR3 and TLR2 signaling in response to F. tularensis. After demonstrating that the model is consistent with experimental results we perform numerical simulations to evaluate the contributions that Akt and Ras-GAP make to ERK inhibition. The model confirms that phagocytosis-associated changes in the composition of the cell membrane can inhibit ERK activity and predicts that Akt and Ras-GAP synergize to inhibit ERK.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1002757