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

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.

Figure 1. Membrane proximal Toll-like Receptor 2 signaling in response to Francisella tularensis: Ligand bound TLR2 () signaling leads to the sequential activation of Rac and Ras GTPases.

Rac and Ras cooperate to activate Raf which leads to ERK activation, while Rac stimulates the PI3K/Akt pathway which antagonizes ERK by inhibiting Raf. The lipid product of PI3K, PIP3, also recruits positive (Vav) and negative (GAP) regulators of Ras and Rac to the immunological synapse. (Red arrows denote inhibition, black arrows denote stimulation.)

Figure 2. Membrane proximal Complement Receptor 3 signaling in response to complement C3-opsonized Francisella tularensis: Complement-bound CR3 () activates Lyn, which leads to the activation of PI3K and the accumulation of PIP3 at the immunological synapse.

PIP3 recruits positive (Vav) and negative (GAP) regulators of Rac, while Rac contributes to PI3K stimulation. (Red arrows denote inhibition, black arrows denote stimulation.)

Figure 3. Membrane proximal CR3/TLR2 crosstalk in response to complement C3-opsonized Francisella tularensis: Ligand bound TLR2 () signaling leads to the sequential activation of Rac and Ras GTPases.

Rac and Ras cooperate to activate Raf, while Rac stimulates the PI3K/Akt pathway. In addition, complement-bound CR3 () activates Lyn, which leads to the activation of PI3K and the accumulation of PIP3 at the immunological synapse. PIP3, recruits positive (Vav) and negative (GAP) regulators of Ras and Rac to the immunological synapse. (In this simplified model active Raf serves as a proxy for active ERK, as explained in the text. Red arrows denote inhibition, black arrows denote stimulation.)

Figure 4. Ras activity in response to unopsonized Francisella.

(, ).

Figure 5. Rac activity in response to unopsonized Francisella.

(, ).

Figure 6. The concentration of 3 Phosphoinositides in response to unopsonozed Francisella.

(, ).

Figure 7. Raf activity in response to unopsonized Francisella.

(, ).

Figure 8. Ras activity in response to complement C3-opsonized Francisella.

(, ).

Figure 9. Rac activity in response to complement C3-opsonized Francisella.

(, ).

Figure 10. The concentration of 3 Phosphoinositides in response to complement C3-opsonozed Francisella.

(, ).

Figure 11. Raf activity in response to complement C3-opsonized Francisella.

(, ).

Figure 12. Scatter plot of rank transformed Raf concentration at 5 minutes post infection versus the rank transformed value of the parameter .

Figure 13. Scatter plot of rank transformed Raf concentration at 5 minutes post infection versus the rank transformed value of the parameter .

Figure 14. Scatter plot of rank transformed Raf concentration at 5 minutes post infection versus the rank transformed value of the parameter .

Figure 15. Scatter plot of rank transformed Raf concentration at 5 minutes post infection versus the rank transformed value of the parameter .