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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 stability of mRNA transcripts controls bacterial load and inflammation by affecting the dynamics of NF-κB-mediated responses. (A) The effect of the stability (half-life) of chemokine mRNA transcripts [t1/2(CHEM)] on the dynamics of chemokine secretion by an individual cell. Simulated results are produced using the single-cell level NF-κB signaling dynamics model for continuous stimulation of a cell by 1 ng/ml TNF, with parameters and equations as described in Tables A3, A5, and A6 in Appendix. A similar pattern of response can be observed when the effects of mRNA stability on the dynamics of other NF-κB-mediated responses (i.e., expression of ACT, IAP, and TNF) are studied (data not shown). (B,C) Simulation results for the effect of the stability of mRNA transcripts corresponding to major NF-κB-mediated responses, including macrophage activation [t1/2(ACT)], TNF expression [t1/2(TNF)], chemokine expression [t1/2(CHEM)], and inhibitor of apoptosis protein expression [t1/2(IAP)], on bacteria numbers (B) and on the activated fraction of macrophages (C) 200 days post-infection. Small squares represent different values of t1/2(CHEM) vertically and different values of t1/2(TNF) horizontally. Large boxes represent different values of t1/2(ACT) vertically and different values of t1/2(IAP) horizontally. Four values of mRNA half-life were tested in simulations: 12 min, 30 min, 1 h, and 3 h. Simulation results were averaged over 10 repetitions. Yellow stars represent an example scenario with containment outcome. This state represents control of infection for more than 200 days within a well-circumscribed granuloma containing stable bacteria numbers (<103 total bacteria). Red stars represent an example scenario that leads to clearance of Mtb (total bacteria = 0) without inducing excessive inflammation (activated fraction of macrophages <0.15).
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Figure 5: The stability of mRNA transcripts controls bacterial load and inflammation by affecting the dynamics of NF-κB-mediated responses. (A) The effect of the stability (half-life) of chemokine mRNA transcripts [t1/2(CHEM)] on the dynamics of chemokine secretion by an individual cell. Simulated results are produced using the single-cell level NF-κB signaling dynamics model for continuous stimulation of a cell by 1 ng/ml TNF, with parameters and equations as described in Tables A3, A5, and A6 in Appendix. A similar pattern of response can be observed when the effects of mRNA stability on the dynamics of other NF-κB-mediated responses (i.e., expression of ACT, IAP, and TNF) are studied (data not shown). (B,C) Simulation results for the effect of the stability of mRNA transcripts corresponding to major NF-κB-mediated responses, including macrophage activation [t1/2(ACT)], TNF expression [t1/2(TNF)], chemokine expression [t1/2(CHEM)], and inhibitor of apoptosis protein expression [t1/2(IAP)], on bacteria numbers (B) and on the activated fraction of macrophages (C) 200 days post-infection. Small squares represent different values of t1/2(CHEM) vertically and different values of t1/2(TNF) horizontally. Large boxes represent different values of t1/2(ACT) vertically and different values of t1/2(IAP) horizontally. Four values of mRNA half-life were tested in simulations: 12 min, 30 min, 1 h, and 3 h. Simulation results were averaged over 10 repetitions. Yellow stars represent an example scenario with containment outcome. This state represents control of infection for more than 200 days within a well-circumscribed granuloma containing stable bacteria numbers (<103 total bacteria). Red stars represent an example scenario that leads to clearance of Mtb (total bacteria = 0) without inducing excessive inflammation (activated fraction of macrophages <0.15).

Mentions: A key advantage of incorporating NF-κB signaling dynamics into our granuloma model is the ability to study the impact of the dynamics of NF-κB-mediated responses (i.e., macrophage activation, expression of chemokines, TNF, and inhibitors of apoptosis) on granuloma outcomes. These responses follow NF-κB oscillations (Nelson et al., 2004). The dynamics of these responses depend, to a large extent, on the stability of their corresponding mRNA transcripts (Hao and Baltimore, 2009). Thus, we analyzed the effect of varying the stability of mRNA transcripts corresponding to macrophage activation (ACT), and expression of chemokines (CHEM), TNF, and inhibitors of apoptosis (IAP) on granuloma outcomes, bacterial load, and inflammation level (represented by the activated fraction of macrophages). Varying the stability (half-life; t1/2) of mRNA transcripts significantly influences the dynamics of the NF-κB-mediated responses (e.g., chemokine secretion) in an individual cell (Figure 5A). Simulations show that the stability of mRNA transcripts for NF-κB-mediated responses, particularly ACT, TNF, and CHEM, significantly control bacteria numbers and inflammation level in tissue (Figures 5B,C). The impact of the IAP mRNA stability on these model outcomes is less significant.


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

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

The stability of mRNA transcripts controls bacterial load and inflammation by affecting the dynamics of NF-κB-mediated responses. (A) The effect of the stability (half-life) of chemokine mRNA transcripts [t1/2(CHEM)] on the dynamics of chemokine secretion by an individual cell. Simulated results are produced using the single-cell level NF-κB signaling dynamics model for continuous stimulation of a cell by 1 ng/ml TNF, with parameters and equations as described in Tables A3, A5, and A6 in Appendix. A similar pattern of response can be observed when the effects of mRNA stability on the dynamics of other NF-κB-mediated responses (i.e., expression of ACT, IAP, and TNF) are studied (data not shown). (B,C) Simulation results for the effect of the stability of mRNA transcripts corresponding to major NF-κB-mediated responses, including macrophage activation [t1/2(ACT)], TNF expression [t1/2(TNF)], chemokine expression [t1/2(CHEM)], and inhibitor of apoptosis protein expression [t1/2(IAP)], on bacteria numbers (B) and on the activated fraction of macrophages (C) 200 days post-infection. Small squares represent different values of t1/2(CHEM) vertically and different values of t1/2(TNF) horizontally. Large boxes represent different values of t1/2(ACT) vertically and different values of t1/2(IAP) horizontally. Four values of mRNA half-life were tested in simulations: 12 min, 30 min, 1 h, and 3 h. Simulation results were averaged over 10 repetitions. Yellow stars represent an example scenario with containment outcome. This state represents control of infection for more than 200 days within a well-circumscribed granuloma containing stable bacteria numbers (<103 total bacteria). Red stars represent an example scenario that leads to clearance of Mtb (total bacteria = 0) without inducing excessive inflammation (activated fraction of macrophages <0.15).
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Related In: Results  -  Collection

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Figure 5: The stability of mRNA transcripts controls bacterial load and inflammation by affecting the dynamics of NF-κB-mediated responses. (A) The effect of the stability (half-life) of chemokine mRNA transcripts [t1/2(CHEM)] on the dynamics of chemokine secretion by an individual cell. Simulated results are produced using the single-cell level NF-κB signaling dynamics model for continuous stimulation of a cell by 1 ng/ml TNF, with parameters and equations as described in Tables A3, A5, and A6 in Appendix. A similar pattern of response can be observed when the effects of mRNA stability on the dynamics of other NF-κB-mediated responses (i.e., expression of ACT, IAP, and TNF) are studied (data not shown). (B,C) Simulation results for the effect of the stability of mRNA transcripts corresponding to major NF-κB-mediated responses, including macrophage activation [t1/2(ACT)], TNF expression [t1/2(TNF)], chemokine expression [t1/2(CHEM)], and inhibitor of apoptosis protein expression [t1/2(IAP)], on bacteria numbers (B) and on the activated fraction of macrophages (C) 200 days post-infection. Small squares represent different values of t1/2(CHEM) vertically and different values of t1/2(TNF) horizontally. Large boxes represent different values of t1/2(ACT) vertically and different values of t1/2(IAP) horizontally. Four values of mRNA half-life were tested in simulations: 12 min, 30 min, 1 h, and 3 h. Simulation results were averaged over 10 repetitions. Yellow stars represent an example scenario with containment outcome. This state represents control of infection for more than 200 days within a well-circumscribed granuloma containing stable bacteria numbers (<103 total bacteria). Red stars represent an example scenario that leads to clearance of Mtb (total bacteria = 0) without inducing excessive inflammation (activated fraction of macrophages <0.15).
Mentions: A key advantage of incorporating NF-κB signaling dynamics into our granuloma model is the ability to study the impact of the dynamics of NF-κB-mediated responses (i.e., macrophage activation, expression of chemokines, TNF, and inhibitors of apoptosis) on granuloma outcomes. These responses follow NF-κB oscillations (Nelson et al., 2004). The dynamics of these responses depend, to a large extent, on the stability of their corresponding mRNA transcripts (Hao and Baltimore, 2009). Thus, we analyzed the effect of varying the stability of mRNA transcripts corresponding to macrophage activation (ACT), and expression of chemokines (CHEM), TNF, and inhibitors of apoptosis (IAP) on granuloma outcomes, bacterial load, and inflammation level (represented by the activated fraction of macrophages). Varying the stability (half-life; t1/2) of mRNA transcripts significantly influences the dynamics of the NF-κB-mediated responses (e.g., chemokine secretion) in an individual cell (Figure 5A). Simulations show that the stability of mRNA transcripts for NF-κB-mediated responses, particularly ACT, TNF, and CHEM, significantly control bacteria numbers and inflammation level in tissue (Figures 5B,C). The impact of the IAP mRNA stability on these model outcomes is less significant.

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