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NF-κB Signaling Dynamics Play a Key Role in Infection Control in Tuberculosis.

Fallahi-Sichani M, Kirschner DE, Linderman JJ - Front Physiol (2012)

Bottom Line: The NF-κB signaling pathway is central to the body's response to many pathogens.We build a multi-scale model of the immune response to the pathogen Mycobacterium tuberculosis (Mtb) to explore the impact of NF-κB dynamics occurring across molecular, cellular, and tissue scales in the lung.We show how the stability of mRNA transcripts corresponding to NF-κB-mediated responses significantly controls bacterial load in a granuloma, inflammation level in tissue, and granuloma size.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Michigan Ann Arbor, MI, USA.

ABSTRACT
The NF-κB signaling pathway is central to the body's response to many pathogens. Mathematical models based on cell culture experiments have identified important molecular mechanisms controlling the dynamics of NF-κB signaling, but the dynamics of this pathway have never been studied in the context of an infection in a host. Here, we incorporate these dynamics into a virtual infection setting. We build a multi-scale model of the immune response to the pathogen Mycobacterium tuberculosis (Mtb) to explore the impact of NF-κB dynamics occurring across molecular, cellular, and tissue scales in the lung. NF-κB signaling is triggered via tumor necrosis factor-α (TNF) binding to receptors on macrophages; TNF has been shown to play a key role in infection dynamics in humans and multiple animal systems. Using our multi-scale model, we predict the impact of TNF-induced NF-κB-mediated responses on the outcome of infection at the level of a granuloma, an aggregate of immune cells and bacteria that forms in response to infection and is key to containment of infection and clinical latency. We show how the stability of mRNA transcripts corresponding to NF-κB-mediated responses significantly controls bacterial load in a granuloma, inflammation level in tissue, and granuloma size. Because we incorporate intracellular signaling pathways explicitly, our analysis also elucidates NF-κB-associated signaling molecules and processes that may be new targets for infection control.

No MeSH data available.


Related in: MedlinePlus

The impact of important processes associated with the NF-κB signaling dynamics on granuloma outcomes is correlated with status of macrophages that undergo apoptosis or become activated by TNF. Simulation results show the effect of (A) the average number of NF-κB molecules per cell, NF-κBtot, (B) IKKK inactivation rate, ki, (C) A20 and IκBα mRNA degradation rate, c3, and (D) TNF mRNA degradation rate, c3rTNF on infected/resting cell ratios Rapoptosis and Ractivation within a 200 day period after Mtb infection.
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Figure 4: The impact of important processes associated with the NF-κB signaling dynamics on granuloma outcomes is correlated with status of macrophages that undergo apoptosis or become activated by TNF. Simulation results show the effect of (A) the average number of NF-κB molecules per cell, NF-κBtot, (B) IKKK inactivation rate, ki, (C) A20 and IκBα mRNA degradation rate, c3, and (D) TNF mRNA degradation rate, c3rTNF on infected/resting cell ratios Rapoptosis and Ractivation within a 200 day period after Mtb infection.

Mentions: How do the NF-κB-associated intracellular processes identified above affect the balance of inflammation and bacterial killing activities within a granuloma? We previously showed that the impact of TNF concentration on granuloma outcomes is strongly correlated with whether or not macrophages stimulated by TNF are infected (Fallahi-Sichani et al., 2011). This motivates us to test whether there is a correlation between the effect of NF-κB signaling dynamics on granuloma function (as described in Figure 3) and the infection status of macrophages stimulated by TNF during the immune response. Thus, we analyze the infection status of macrophages that become activated or undergo apoptosis after Mtb infection by computing infected/resting cell ratios, Ractivation and Rapoptosis, as defined in Section “Materials and Methods.” Our model predicts a very significant effect of important NF-κB-associated parameters on both Ractivation and Rapoptosis (Figure 4). At small numbers of NF-κB molecules per cell, slow rates of A20 and IκBα mRNA degradation, rapid rates of IKKK inactivation, or rapid rates of TNF mRNA degradation, infected macrophages are the main cells that become activated or undergo apoptosis as a result of TNF activities (Ractivation and Rapoptosis ≫ 1). However, with one order of magnitude increase in each of these parameters, resting macrophages become the main responders to TNF signaling (Ractivation and Rapoptosis ≪ 1). Comparing these results with results from the previous section (Figure 3), we observe a significant correlation between infected/resting cell ratios, Ractivation and Rapoptosis, and the granuloma outcomes (i.e., bacterial load and inflammation). At large values of Ractivation and Rapoptosis (values of 1–10 or greater), we observe uncontrolled growth of Mtb. Small values of these ratios (smaller than ∼0.1) correlate with excessive inflammation in tissue. Intermediate values of infected/resting cell ratios (between 0.1 and 1) are correlated with control of infection without excessive inflammation. The absolute values of these ratios are calculated based on our two-dimensional simulations and might change in three-dimensional settings. These results suggest that a balance between the number of resting macrophages and infected macrophages responding to TNF signaling is required for control of infection and inflammation within a stable granuloma, and that such a balance is critically regulated by NF-κB signaling dynamics.


NF-κB Signaling Dynamics Play a Key Role in Infection Control in Tuberculosis.

Fallahi-Sichani M, Kirschner DE, Linderman JJ - Front Physiol (2012)

The impact of important processes associated with the NF-κB signaling dynamics on granuloma outcomes is correlated with status of macrophages that undergo apoptosis or become activated by TNF. Simulation results show the effect of (A) the average number of NF-κB molecules per cell, NF-κBtot, (B) IKKK inactivation rate, ki, (C) A20 and IκBα mRNA degradation rate, c3, and (D) TNF mRNA degradation rate, c3rTNF on infected/resting cell ratios Rapoptosis and Ractivation within a 200 day period after Mtb infection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368390&req=5

Figure 4: The impact of important processes associated with the NF-κB signaling dynamics on granuloma outcomes is correlated with status of macrophages that undergo apoptosis or become activated by TNF. Simulation results show the effect of (A) the average number of NF-κB molecules per cell, NF-κBtot, (B) IKKK inactivation rate, ki, (C) A20 and IκBα mRNA degradation rate, c3, and (D) TNF mRNA degradation rate, c3rTNF on infected/resting cell ratios Rapoptosis and Ractivation within a 200 day period after Mtb infection.
Mentions: How do the NF-κB-associated intracellular processes identified above affect the balance of inflammation and bacterial killing activities within a granuloma? We previously showed that the impact of TNF concentration on granuloma outcomes is strongly correlated with whether or not macrophages stimulated by TNF are infected (Fallahi-Sichani et al., 2011). This motivates us to test whether there is a correlation between the effect of NF-κB signaling dynamics on granuloma function (as described in Figure 3) and the infection status of macrophages stimulated by TNF during the immune response. Thus, we analyze the infection status of macrophages that become activated or undergo apoptosis after Mtb infection by computing infected/resting cell ratios, Ractivation and Rapoptosis, as defined in Section “Materials and Methods.” Our model predicts a very significant effect of important NF-κB-associated parameters on both Ractivation and Rapoptosis (Figure 4). At small numbers of NF-κB molecules per cell, slow rates of A20 and IκBα mRNA degradation, rapid rates of IKKK inactivation, or rapid rates of TNF mRNA degradation, infected macrophages are the main cells that become activated or undergo apoptosis as a result of TNF activities (Ractivation and Rapoptosis ≫ 1). However, with one order of magnitude increase in each of these parameters, resting macrophages become the main responders to TNF signaling (Ractivation and Rapoptosis ≪ 1). Comparing these results with results from the previous section (Figure 3), we observe a significant correlation between infected/resting cell ratios, Ractivation and Rapoptosis, and the granuloma outcomes (i.e., bacterial load and inflammation). At large values of Ractivation and Rapoptosis (values of 1–10 or greater), we observe uncontrolled growth of Mtb. Small values of these ratios (smaller than ∼0.1) correlate with excessive inflammation in tissue. Intermediate values of infected/resting cell ratios (between 0.1 and 1) are correlated with control of infection without excessive inflammation. The absolute values of these ratios are calculated based on our two-dimensional simulations and might change in three-dimensional settings. These results suggest that a balance between the number of resting macrophages and infected macrophages responding to TNF signaling is required for control of infection and inflammation within a stable granuloma, and that such a balance is critically regulated by NF-κB signaling dynamics.

Bottom Line: The NF-κB signaling pathway is central to the body's response to many pathogens.We build a multi-scale model of the immune response to the pathogen Mycobacterium tuberculosis (Mtb) to explore the impact of NF-κB dynamics occurring across molecular, cellular, and tissue scales in the lung.We show how the stability of mRNA transcripts corresponding to NF-κB-mediated responses significantly controls bacterial load in a granuloma, inflammation level in tissue, and granuloma size.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Michigan Ann Arbor, MI, USA.

ABSTRACT
The NF-κB signaling pathway is central to the body's response to many pathogens. Mathematical models based on cell culture experiments have identified important molecular mechanisms controlling the dynamics of NF-κB signaling, but the dynamics of this pathway have never been studied in the context of an infection in a host. Here, we incorporate these dynamics into a virtual infection setting. We build a multi-scale model of the immune response to the pathogen Mycobacterium tuberculosis (Mtb) to explore the impact of NF-κB dynamics occurring across molecular, cellular, and tissue scales in the lung. NF-κB signaling is triggered via tumor necrosis factor-α (TNF) binding to receptors on macrophages; TNF has been shown to play a key role in infection dynamics in humans and multiple animal systems. Using our multi-scale model, we predict the impact of TNF-induced NF-κB-mediated responses on the outcome of infection at the level of a granuloma, an aggregate of immune cells and bacteria that forms in response to infection and is key to containment of infection and clinical latency. We show how the stability of mRNA transcripts corresponding to NF-κB-mediated responses significantly controls bacterial load in a granuloma, inflammation level in tissue, and granuloma size. Because we incorporate intracellular signaling pathways explicitly, our analysis also elucidates NF-κB-associated signaling molecules and processes that may be new targets for infection control.

No MeSH data available.


Related in: MedlinePlus