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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

Optimal regulation of the TNF-mediated NF-κB signaling dynamics is essential for optimal granuloma outcomes. Impaired NF-κB activity leads to uncontrolled growth of bacteria within a granuloma (outcome I). Containment or clearance of bacteria (outcome II) is achieved when the NF-κB-mediated responses are regulated such that small, but sufficient numbers of macrophages become activated to kill bacteria. Uncontrolled macrophage activation due to over-activity of NF-κB leads to excessive inflammation in tissue (outcome III).
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Figure 8: Optimal regulation of the TNF-mediated NF-κB signaling dynamics is essential for optimal granuloma outcomes. Impaired NF-κB activity leads to uncontrolled growth of bacteria within a granuloma (outcome I). Containment or clearance of bacteria (outcome II) is achieved when the NF-κB-mediated responses are regulated such that small, but sufficient numbers of macrophages become activated to kill bacteria. Uncontrolled macrophage activation due to over-activity of NF-κB leads to excessive inflammation in tissue (outcome III).

Mentions: Immune responses induced by Mtb infection are myriad and complex, and it remains incompletely understood which responses are required for protection and which contribute to pathology (Cooper, 2009; Lin and Flynn, 2010). Indeed, there is significant overlap among protective and pathological responses. An important example, as dissected in this study, is TNF-induced NF-κB activation. Figure 8 summarizes our results showing how NF-κB-mediated responses are critical for restricting bacterial growth in a granuloma, but excessive activation of the NF-κB pathway in macrophages leads to pathological inflammation in tissue. Containment of bacteria, particularly at the level of the granuloma, is achieved when a balance exists between the NF-κB-mediated bacterial killing activities and the NF-κB-mediated inflammation. Such a balance is controlled by a combination of molecular scale biochemical processes identified in detail in this study, such as IKKK activity, A20 and IκBα interactions, and stability of mRNA transcripts associated with NF-κB-mediated responses. Optimal regulation of these processes, in the presence of an efficient T cell-meditated response, can lead to clearance of bacteria. Further, we find that processes controlling the dynamics of NF-κB signaling critically regulate whether resting macrophages or infected macrophages are the major targets for TNF signaling within a granuloma. Unless sufficient numbers of resting macrophages relative to infected macrophages become activated by TNF, uncontrolled growth of Mtb occurs. On the other hand, excessive activation of resting macrophages leads to uncontrolled inflammation. These findings highlight the potential importance of NF-κB-associated processes as targets in future studies examining approaches to controlling both TB infection and pathology.


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

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

Optimal regulation of the TNF-mediated NF-κB signaling dynamics is essential for optimal granuloma outcomes. Impaired NF-κB activity leads to uncontrolled growth of bacteria within a granuloma (outcome I). Containment or clearance of bacteria (outcome II) is achieved when the NF-κB-mediated responses are regulated such that small, but sufficient numbers of macrophages become activated to kill bacteria. Uncontrolled macrophage activation due to over-activity of NF-κB leads to excessive inflammation in tissue (outcome III).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Optimal regulation of the TNF-mediated NF-κB signaling dynamics is essential for optimal granuloma outcomes. Impaired NF-κB activity leads to uncontrolled growth of bacteria within a granuloma (outcome I). Containment or clearance of bacteria (outcome II) is achieved when the NF-κB-mediated responses are regulated such that small, but sufficient numbers of macrophages become activated to kill bacteria. Uncontrolled macrophage activation due to over-activity of NF-κB leads to excessive inflammation in tissue (outcome III).
Mentions: Immune responses induced by Mtb infection are myriad and complex, and it remains incompletely understood which responses are required for protection and which contribute to pathology (Cooper, 2009; Lin and Flynn, 2010). Indeed, there is significant overlap among protective and pathological responses. An important example, as dissected in this study, is TNF-induced NF-κB activation. Figure 8 summarizes our results showing how NF-κB-mediated responses are critical for restricting bacterial growth in a granuloma, but excessive activation of the NF-κB pathway in macrophages leads to pathological inflammation in tissue. Containment of bacteria, particularly at the level of the granuloma, is achieved when a balance exists between the NF-κB-mediated bacterial killing activities and the NF-κB-mediated inflammation. Such a balance is controlled by a combination of molecular scale biochemical processes identified in detail in this study, such as IKKK activity, A20 and IκBα interactions, and stability of mRNA transcripts associated with NF-κB-mediated responses. Optimal regulation of these processes, in the presence of an efficient T cell-meditated response, can lead to clearance of bacteria. Further, we find that processes controlling the dynamics of NF-κB signaling critically regulate whether resting macrophages or infected macrophages are the major targets for TNF signaling within a granuloma. Unless sufficient numbers of resting macrophages relative to infected macrophages become activated by TNF, uncontrolled growth of Mtb occurs. On the other hand, excessive activation of resting macrophages leads to uncontrolled inflammation. These findings highlight the potential importance of NF-κB-associated processes as targets in future studies examining approaches to controlling both TB infection and pathology.

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