Limits...
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

Schematic diagram of the multi-scale model of the immune response to Mtb infection in the lung. (A) An overview of selected cell- and tissue-level ABM rules based on known immunological activities and interactions (Mr, resting macrophage; Mi, infected macrophage; Mci, chronically infected macrophage; Ma, activated macrophage; Tγ, pro-inflammatory IFN-γ producing T cell; Tc, cytotoxic T cell). Example rules are: (I) infection of a resting macrophage after phagocytosis of extracellular Mtb, (II) intracellular growth of Mtb within an infected macrophage, (III) cytotoxic T cell-mediated killing of an infected macrophage, (IV) activation of a macrophage as a result of interaction with IFN-γ producing T cells and TNF, (V) secretion of TNF (and chemokines) from an activated macrophage and diffusion in tissue, (VI) TNF interactions with a macrophage and induction of feedback mechanisms that control TNF-mediated cell responses. For a full description of all ABM rules (see Fallahi-Sichani et al., 2011). (B) An overview of TNF/TNFR binding and trafficking interactions and reactions and the NF-κB signal transduction cascade at the level of individual cell. TNF/TNFR-associated processes are modeled in both macrophages and T cells. (C) Detailed description of the regulation of the TNF-induced NF-κB signaling pathway and NF-κB-mediated responses [expression of chemokines (CHEM), TNF, inhibitors of apoptosis (IAP), and macrophage-activating molecules (ACT)] for an individual macrophage.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3368390&req=5

Figure 1: Schematic diagram of the multi-scale model of the immune response to Mtb infection in the lung. (A) An overview of selected cell- and tissue-level ABM rules based on known immunological activities and interactions (Mr, resting macrophage; Mi, infected macrophage; Mci, chronically infected macrophage; Ma, activated macrophage; Tγ, pro-inflammatory IFN-γ producing T cell; Tc, cytotoxic T cell). Example rules are: (I) infection of a resting macrophage after phagocytosis of extracellular Mtb, (II) intracellular growth of Mtb within an infected macrophage, (III) cytotoxic T cell-mediated killing of an infected macrophage, (IV) activation of a macrophage as a result of interaction with IFN-γ producing T cells and TNF, (V) secretion of TNF (and chemokines) from an activated macrophage and diffusion in tissue, (VI) TNF interactions with a macrophage and induction of feedback mechanisms that control TNF-mediated cell responses. For a full description of all ABM rules (see Fallahi-Sichani et al., 2011). (B) An overview of TNF/TNFR binding and trafficking interactions and reactions and the NF-κB signal transduction cascade at the level of individual cell. TNF/TNFR-associated processes are modeled in both macrophages and T cells. (C) Detailed description of the regulation of the TNF-induced NF-κB signaling pathway and NF-κB-mediated responses [expression of chemokines (CHEM), TNF, inhibitors of apoptosis (IAP), and macrophage-activating molecules (ACT)] for an individual macrophage.

Mentions: One can hypothesize that molecules such as NF-κB that have been shown to be critical to immunity against Mtb may have significant effects at the cell and tissue scale, namely on the formation and function of granulomas (Barry et al., 2009; Kirschner et al., 2010). However, these effects have not been identified. For example, it is unclear how the dynamics of NF-κB-mediated responses (i.e., expression of chemokines, TNF and IAPs, and activation of macrophages) affect formation and function of a granuloma. A critical requirement for such studies is the integration of biological information across multiple biological scales (molecular, cellular, and tissue; Figure 1). In this study, we describe a multi-scale computational model that includes: (i) molecular interactions describing the dynamics of the TNF-induced NF-κB signaling pathway, (ii) molecular interactions describing the dynamics of TNFR binding and trafficking, and (iii) cellular/tissue-scale dynamics of the immune response to Mtb. These processes altogether lead to formation of a granuloma. We incorporate a recent model of the NF-κB pathway developed by Tay et al. (2010) based on cell culture data but never explored in the context of an infection in a host. We show that dynamics of TNF-induced NF-κB signaling are critical to controlling bacterial load and inflammation levels at the tissue scale. Further, TNF-mediated activation of resting macrophages, in addition to infected macrophages, is required for a protective immune response, but must be optimally regulated by the immune system to prevent excessive inflammation. We also predict the impact of the dynamics (the extent and the timing) of various NF-κB-mediated responses (i.e., expression of chemokines, TNF, IAPs, and activation of macrophages) on both formation and function of a granuloma. Finally, we ask whether pharmacologically manipulating the NF-κB signaling pathway (for example, by affecting mRNA stability) can improve the outcome of a granuloma that is initially unable to control infection.


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

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

Schematic diagram of the multi-scale model of the immune response to Mtb infection in the lung. (A) An overview of selected cell- and tissue-level ABM rules based on known immunological activities and interactions (Mr, resting macrophage; Mi, infected macrophage; Mci, chronically infected macrophage; Ma, activated macrophage; Tγ, pro-inflammatory IFN-γ producing T cell; Tc, cytotoxic T cell). Example rules are: (I) infection of a resting macrophage after phagocytosis of extracellular Mtb, (II) intracellular growth of Mtb within an infected macrophage, (III) cytotoxic T cell-mediated killing of an infected macrophage, (IV) activation of a macrophage as a result of interaction with IFN-γ producing T cells and TNF, (V) secretion of TNF (and chemokines) from an activated macrophage and diffusion in tissue, (VI) TNF interactions with a macrophage and induction of feedback mechanisms that control TNF-mediated cell responses. For a full description of all ABM rules (see Fallahi-Sichani et al., 2011). (B) An overview of TNF/TNFR binding and trafficking interactions and reactions and the NF-κB signal transduction cascade at the level of individual cell. TNF/TNFR-associated processes are modeled in both macrophages and T cells. (C) Detailed description of the regulation of the TNF-induced NF-κB signaling pathway and NF-κB-mediated responses [expression of chemokines (CHEM), TNF, inhibitors of apoptosis (IAP), and macrophage-activating molecules (ACT)] for an individual macrophage.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Schematic diagram of the multi-scale model of the immune response to Mtb infection in the lung. (A) An overview of selected cell- and tissue-level ABM rules based on known immunological activities and interactions (Mr, resting macrophage; Mi, infected macrophage; Mci, chronically infected macrophage; Ma, activated macrophage; Tγ, pro-inflammatory IFN-γ producing T cell; Tc, cytotoxic T cell). Example rules are: (I) infection of a resting macrophage after phagocytosis of extracellular Mtb, (II) intracellular growth of Mtb within an infected macrophage, (III) cytotoxic T cell-mediated killing of an infected macrophage, (IV) activation of a macrophage as a result of interaction with IFN-γ producing T cells and TNF, (V) secretion of TNF (and chemokines) from an activated macrophage and diffusion in tissue, (VI) TNF interactions with a macrophage and induction of feedback mechanisms that control TNF-mediated cell responses. For a full description of all ABM rules (see Fallahi-Sichani et al., 2011). (B) An overview of TNF/TNFR binding and trafficking interactions and reactions and the NF-κB signal transduction cascade at the level of individual cell. TNF/TNFR-associated processes are modeled in both macrophages and T cells. (C) Detailed description of the regulation of the TNF-induced NF-κB signaling pathway and NF-κB-mediated responses [expression of chemokines (CHEM), TNF, inhibitors of apoptosis (IAP), and macrophage-activating molecules (ACT)] for an individual macrophage.
Mentions: One can hypothesize that molecules such as NF-κB that have been shown to be critical to immunity against Mtb may have significant effects at the cell and tissue scale, namely on the formation and function of granulomas (Barry et al., 2009; Kirschner et al., 2010). However, these effects have not been identified. For example, it is unclear how the dynamics of NF-κB-mediated responses (i.e., expression of chemokines, TNF and IAPs, and activation of macrophages) affect formation and function of a granuloma. A critical requirement for such studies is the integration of biological information across multiple biological scales (molecular, cellular, and tissue; Figure 1). In this study, we describe a multi-scale computational model that includes: (i) molecular interactions describing the dynamics of the TNF-induced NF-κB signaling pathway, (ii) molecular interactions describing the dynamics of TNFR binding and trafficking, and (iii) cellular/tissue-scale dynamics of the immune response to Mtb. These processes altogether lead to formation of a granuloma. We incorporate a recent model of the NF-κB pathway developed by Tay et al. (2010) based on cell culture data but never explored in the context of an infection in a host. We show that dynamics of TNF-induced NF-κB signaling are critical to controlling bacterial load and inflammation levels at the tissue scale. Further, TNF-mediated activation of resting macrophages, in addition to infected macrophages, is required for a protective immune response, but must be optimally regulated by the immune system to prevent excessive inflammation. We also predict the impact of the dynamics (the extent and the timing) of various NF-κB-mediated responses (i.e., expression of chemokines, TNF, IAPs, and activation of macrophages) on both formation and function of a granuloma. Finally, we ask whether pharmacologically manipulating the NF-κB signaling pathway (for example, by affecting mRNA stability) can improve the outcome of a granuloma that is initially unable to control infection.

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