Multi-scale modeling predicts a balance of tumor necrosis factor-α and interleukin-10 controls the granuloma environment during Mycobacterium tuberculosis infection

Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) are key anti- and pro-inflammatory mediators elicited during the host immune response to Mycobacterium tuberculosis (Mtb). Understanding the opposing effects of these mediators is difficult due to the complexity of processes acting across di...

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Bibliographic Details
Published in:PloS one 2013-07, Vol.8 (7), p.e68680-e68680
Main Authors: Cilfone, Nicholas A, Perry, Cory R, Kirschner, Denise E, Linderman, Jennifer J
Format: Article
Language:English
Subjects:
Agent-based models
Apoptosis
Bacteria
Biology
Cell activation
Chemical engineering
Chemokines
Computational Biology
Cytokines
Damage prevention
Granuloma
Granuloma - metabolism
Granuloma - pathology
Humans
Immune response
Immune system
Immunology
Infections
Inflammation
Interleukin 10
Interleukin-10 - metabolism
Interleukin-10 - physiology
Lungs
Lymphocytes
Macrophages
Macrophages - immunology
Mathematical models
Mathematics
Medicine
Models, Theoretical
Multi-scale models
Mycobacterium tuberculosis
Mycobacterium tuberculosis - immunology
Necrosis
Scale models
Signal Transduction
Signaling
Spatial distribution
Tuberculosis
Tuberculosis - metabolism
Tuberculosis - pathology
Tumor Necrosis Factor-alpha - metabolism
Tumor Necrosis Factor-alpha - physiology
Tumor necrosis factor-TNF
Tumor necrosis factor-α
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Summary:Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) are key anti- and pro-inflammatory mediators elicited during the host immune response to Mycobacterium tuberculosis (Mtb). Understanding the opposing effects of these mediators is difficult due to the complexity of processes acting across different spatial (molecular, cellular, and tissue) and temporal (seconds to years) scales. We take an in silico approach and use multi-scale agent based modeling of the immune response to Mtb, including molecular scale details for both TNF-α and IL-10. Our model predicts that IL-10 is necessary to modulate macrophage activation levels and to prevent host-induced tissue damage in a granuloma, an aggregate of cells that forms in response to Mtb. We show that TNF-α and IL-10 parameters related to synthesis, signaling, and spatial distribution processes control concentrations of TNF-α and IL-10 in a granuloma and determine infection outcome in the long-term. We devise an overall measure of granuloma function based on three metrics - total bacterial load, macrophage activation levels, and apoptosis of resting macrophages - and use this metric to demonstrate a balance of TNF-α and IL-10 concentrations is essential to Mtb infection control, within a single granuloma, with minimal host-induced tissue damage. Our findings suggest that a balance of TNF-α and IL-10 defines a granuloma environment that may be beneficial for both host and pathogen, but perturbing the balance could be used as a novel therapeutic strategy to modulate infection outcomes.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0068680