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

Overview

Journal PLoS Comput Biol

Specialty Biology

Date 2012 Nov 8

PMID 23133361

Citations 11

Authors

Rachel Leander

Shipan Dai

Larry S Schlesinger

Avner Friedman

Affiliations

Soon will be listed here.

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.

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References

Dougherty M, Muller J, Ritt D, Zhou M, Zhou X, Copeland T . Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005; 17(2):215-24. DOI: 10.1016/j.molcel.2004.11.055. View

Clemens D, Horwitz M . Uptake and intracellular fate of Francisella tularensis in human macrophages. Ann N Y Acad Sci. 2007; 1105:160-86. DOI: 10.1196/annals.1409.001. View

Gordon D, JOHNSON G, Hostetter M . Ligand-receptor interactions in the phagocytosis of virulent Streptococcus pneumoniae by polymorphonuclear leukocytes. J Infect Dis. 1986; 154(4):619-26. DOI: 10.1093/infdis/154.4.619. View

Hall A, Gakidis M, Glogauer M, Wilsbacher J, Gao S, Swat W . Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR- and complement-mediated phagocytosis. Immunity. 2006; 24(3):305-16. DOI: 10.1016/j.immuni.2006.02.005. View

Hajishengallis G, Lambris J . Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol. 2011; 11(3):187-200. PMC: 3077082. DOI: 10.1038/nri2918. View

Schoeberl B, Eichler-Jonsson C, Gilles E, Muller G . Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nat Biotechnol. 2002; 20(4):370-5. DOI: 10.1038/nbt0402-370. View

Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M . Regulation of Raf-Akt Cross-talk. J Biol Chem. 2002; 277(34):31099-106. DOI: 10.1074/jbc.M111974200. View

Hajishengallis G, Lambris J . Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 2010; 31(4):154-63. PMC: 2849859. DOI: 10.1016/j.it.2010.01.002. View

Stephens L, Hughes K, Irvine R . Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature. 1991; 351(6321):33-9. DOI: 10.1038/351033a0. View

10.

Zeidler R, Kim H . Phagocytosis, chemiluminescence, and cell volume of alveolar macrophages from neonatal and adult pigs. J Leukoc Biol. 1985; 37(1):29-43. DOI: 10.1002/jlb.37.1.29. View

11.

Visintin A, Mazzoni A, Spitzer J, Wyllie D, Dower S, Segal D . Regulation of Toll-like receptors in human monocytes and dendritic cells. J Immunol. 2000; 166(1):249-55. DOI: 10.4049/jimmunol.166.1.249. View

12.

Chen B, Kang J, Lu Y, Hsu M, Liao C, Chiu W . Rac1 regulates peptidoglycan-induced nuclear factor-kappaB activation and cyclooxygenase-2 expression in RAW 264.7 macrophages by activating the phosphatidylinositol 3-kinase/Akt pathway. Mol Immunol. 2009; 46(6):1179-88. DOI: 10.1016/j.molimm.2008.11.006. View

13.

Krugmann S, Anderson K, Ridley S, Risso N, McGregor A, Coadwell J . Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. Mol Cell. 2002; 9(1):95-108. DOI: 10.1016/s1097-2765(02)00434-3. View

14.

Schlesinger L, Horwitz M . Phagocytosis of leprosy bacilli is mediated by complement receptors CR1 and CR3 on human monocytes and complement component C3 in serum. J Clin Invest. 1990; 85(4):1304-14. PMC: 296567. DOI: 10.1172/JCI114568. View

15.

Lemmon M . Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol. 2008; 9(2):99-111. DOI: 10.1038/nrm2328. View

16.

I S, Nie Z, Stewart A, Najdovska M, Hall N, He H . ARAP3 is transiently tyrosine phosphorylated in cells attaching to fibronectin and inhibits cell spreading in a RhoGAP-dependent manner. J Cell Sci. 2004; 117(Pt 25):6071-84. DOI: 10.1242/jcs.01526. View

17.

Cvejic S, Jiang Y, Huang X . Signaling of G(alpha)(12) family of G proteins through a tyrosine kinase and a Ras-GAP. Trends Cardiovasc Med. 2001; 10(4):160-5. DOI: 10.1016/s1050-1738(00)00054-2. View

18.

Seoh M, Ng C, Yong J, Lim L, Leung T . ArhGAP15, a novel human RacGAP protein with GTPase binding property. FEBS Lett. 2003; 539(1-3):131-7. DOI: 10.1016/s0014-5793(03)00213-8. View

19.

Kaufman R, Davies M, Pathak V, Hershey J . The phosphorylation state of eucaryotic initiation factor 2 alters translational efficiency of specific mRNAs. Mol Cell Biol. 1989; 9(3):946-58. PMC: 362683. DOI: 10.1128/mcb.9.3.946-958.1989. View

20.

Cai T, Wright S . Energetics of leukocyte integrin activation. J Biol Chem. 1995; 270(24):14358-65. DOI: 10.1074/jbc.270.24.14358. View