A Mathematical Model of CR3/TLR2 Crosstalk in the Context of Francisella tularensis Infection

被引:13
|
作者
Leander, Rachel [1 ]
Dai, Shipan [2 ]
Schlesinger, Larry S. [2 ]
Friedman, Avner [1 ]
机构
[1] Ohio State Univ, Math Biosci Inst, Columbus, OH 43210 USA
[2] Ohio State Univ, Ctr Microbial Interface Biol, Dept Microbial Infect & Immun, Columbus, OH 43210 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
TOLL-LIKE RECEPTORS; GTPASE-ACTIVATING PROTEINS; TYROSINE KINASE; COMPLEMENT RECEPTOR-3; PLECKSTRIN HOMOLOGY; ALVEOLAR MACROPHAGES; MYCOBACTERIUM-TUBERCULOSIS; FEEDBACK-REGULATION; PLASMA-MEMBRANE; HUMAN MONOCYTES;
D O I
10.1371/journal.pcbi.1002757
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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. Citation: Leander R, Dai S, Schlesinger LS, Friedman A (2012) A Mathematical Model of CR3/TLR2 Crosstalk in the Context of Francisella tularensis Infection. PLoS Comput Biol 8(11): e1002757. doi:10.1371/journal.pcbi.1002757
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页数:19
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