Abstract
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.
Highlights
Receptor-mediated engagement followed by phagocytosis by professional phagocytes is the first critical step in microbial clearance or, in the case of intracellular pathogens, entry to a safe niche
In the current work we construct a highly contextual model of membrane-proximal crosstalk between the ERK and PI3K cascades that is initiated through contact with F. tularensis
The model is used to test the hypothesis that phagocytic signaling downstream from Complement Receptor 3 (CR3) is responsible for an early inhibition of ERK activity, which is seen subsequent to contact with the complement C3-opsonized Schu S4 strain of F. tularensis
Summary
Receptor-mediated engagement followed by phagocytosis by professional phagocytes is the first critical step in microbial clearance or, in the case of intracellular pathogens, entry to a safe niche. The molecular mechanisms underlying phagocytosis are complex, usually involving more than one receptor and rapidly culminating in the combinatorial generation of a variety of biochemical signals along with rearrangement of the actin cytoskeleton to engulf the microbe [1]. There are substantial differences in cellular responses for almost every phagocytic receptor used, and complex interactions between receptors can be expected since a variety of ligands usually coat microbes. In this context, computational modeling becomes an essential tool through which experimentalists can enhance their understanding. The mechanisms by which CR3 regulates TLR signaling are an area of active research, in part because CR3/TLR crosstalk is implicated in the pathogenesis of several diseases
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