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Predicting the Role of IL-10 in the Regulation of the Adaptive Immune Responses in Mycobacterium avium Subsp. paratuberculosis Infections Using Mathematical Models.

Magombedze G, Eda S, Stabel J - PLoS ONE (2015)

Bottom Line: The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type).We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011).In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, 37996-1527, United States of America.

ABSTRACT
Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular bacterial pathogen that causes Johne's disease (JD) in cattle and other animals. The hallmark of MAP infection in the early stages is a strong protective cell-mediated immune response (Th1-type), characterized by antigen-specific γ-interferon (IFN-γ). The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type). Interleukin-10 (IL-10) is believed to play a critical role in the regulation of host immune responses to MAP infection and potentially orchestrate the reversal of Th1/Th2 immune dominance during disease progression. However, how its role correlates with MAP infection remains to be completely deciphered. We developed mathematical models to explain probable mechanisms for IL-10 involvement in MAP infection. We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011). Our models predicted that IL-10 can have different roles during MAP infection, (i) it can suppress the Th1 expression, (ii) can enhance Th2 (IL-4) expression, and (iii) can suppress the Th1 expression in synergy with IL-4. In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP. We also predicted that Th1-mediated responses (IFN-γ) can lead to high expression of IL-10 and that infection burden regulates Th2 suppression by the Th1 response. Our models highlight areas where more experimental data is required to refine our model assumptions, and further test and investigate the role of IL-10 in MAP infection.

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An illustration of the effect of IL-10 Th1 inhibition.Simulations showing the effect of IL10 inhibition on Th1 cells and how this translates to other cell populations and CFU shedding. Increasing IL-10 inhibition on Th1 cells results in reduced Th1 expression. Suppression of Th1 response is followed by a high density of infected macrophages, extracellular bacteria, and Th2 expression. These changes explain the increased MAP (CFU) shedding. Simulations were generated using the cell compartmental model with the assumption that IL-10 inhibits Th1. IL-10 inhibition is modelled by increasing the inhibition parameter, a1 from 0 (no inhibition) to 0.005 (+IL-10 inhibition) while the rest of the model parameters are kept at the baseline values given in Table 2. The yellow shading shows the effects (population increase or reduction) as a result of IL-10 inhibition. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL-10, green-Th2 cells, pink-infected macrophages.
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pone.0141539.g004: An illustration of the effect of IL-10 Th1 inhibition.Simulations showing the effect of IL10 inhibition on Th1 cells and how this translates to other cell populations and CFU shedding. Increasing IL-10 inhibition on Th1 cells results in reduced Th1 expression. Suppression of Th1 response is followed by a high density of infected macrophages, extracellular bacteria, and Th2 expression. These changes explain the increased MAP (CFU) shedding. Simulations were generated using the cell compartmental model with the assumption that IL-10 inhibits Th1. IL-10 inhibition is modelled by increasing the inhibition parameter, a1 from 0 (no inhibition) to 0.005 (+IL-10 inhibition) while the rest of the model parameters are kept at the baseline values given in Table 2. The yellow shading shows the effects (population increase or reduction) as a result of IL-10 inhibition. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL-10, green-Th2 cells, pink-infected macrophages.

Mentions: Fig 4 shows the effect of IL-10 inhibition on Th1 responses (assuming that IL-10 is expressed in MAP infections and its role is to suppress Th1 (IFN-γ) expression). Suppression of Th1 by IL-10 is shown to be associated with increased MAP infection. When IL-10 inhibition is increased the density of infected macrophages, free bacteria, Th2 expression and CFU shedding are increased while Th1 expression diminishes. This result also shows that high expression of IL-10 is matched with a corresponding expression of the Th1 response and the decline in the Th1 expression is followed by a drop in IL-10 expression. This observation from our model is consistent with observations from experimental studies [7, 20], which showed high expression of both IL-10 and IFN-γ. Since the Th1 response is protective, its high expression will be matched by less CFU shedding. If the role of IL-10 is to suppress or inhibit IFN-γ (Th1), then when Th1 expression decreases, the bacterial load will increase with increasing Th2 (which is assumed not to be protective). Increasing bacteria results in more infected macrophages hence increased CFU shedding.


Predicting the Role of IL-10 in the Regulation of the Adaptive Immune Responses in Mycobacterium avium Subsp. paratuberculosis Infections Using Mathematical Models.

Magombedze G, Eda S, Stabel J - PLoS ONE (2015)

An illustration of the effect of IL-10 Th1 inhibition.Simulations showing the effect of IL10 inhibition on Th1 cells and how this translates to other cell populations and CFU shedding. Increasing IL-10 inhibition on Th1 cells results in reduced Th1 expression. Suppression of Th1 response is followed by a high density of infected macrophages, extracellular bacteria, and Th2 expression. These changes explain the increased MAP (CFU) shedding. Simulations were generated using the cell compartmental model with the assumption that IL-10 inhibits Th1. IL-10 inhibition is modelled by increasing the inhibition parameter, a1 from 0 (no inhibition) to 0.005 (+IL-10 inhibition) while the rest of the model parameters are kept at the baseline values given in Table 2. The yellow shading shows the effects (population increase or reduction) as a result of IL-10 inhibition. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL-10, green-Th2 cells, pink-infected macrophages.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664406&req=5

pone.0141539.g004: An illustration of the effect of IL-10 Th1 inhibition.Simulations showing the effect of IL10 inhibition on Th1 cells and how this translates to other cell populations and CFU shedding. Increasing IL-10 inhibition on Th1 cells results in reduced Th1 expression. Suppression of Th1 response is followed by a high density of infected macrophages, extracellular bacteria, and Th2 expression. These changes explain the increased MAP (CFU) shedding. Simulations were generated using the cell compartmental model with the assumption that IL-10 inhibits Th1. IL-10 inhibition is modelled by increasing the inhibition parameter, a1 from 0 (no inhibition) to 0.005 (+IL-10 inhibition) while the rest of the model parameters are kept at the baseline values given in Table 2. The yellow shading shows the effects (population increase or reduction) as a result of IL-10 inhibition. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL-10, green-Th2 cells, pink-infected macrophages.
Mentions: Fig 4 shows the effect of IL-10 inhibition on Th1 responses (assuming that IL-10 is expressed in MAP infections and its role is to suppress Th1 (IFN-γ) expression). Suppression of Th1 by IL-10 is shown to be associated with increased MAP infection. When IL-10 inhibition is increased the density of infected macrophages, free bacteria, Th2 expression and CFU shedding are increased while Th1 expression diminishes. This result also shows that high expression of IL-10 is matched with a corresponding expression of the Th1 response and the decline in the Th1 expression is followed by a drop in IL-10 expression. This observation from our model is consistent with observations from experimental studies [7, 20], which showed high expression of both IL-10 and IFN-γ. Since the Th1 response is protective, its high expression will be matched by less CFU shedding. If the role of IL-10 is to suppress or inhibit IFN-γ (Th1), then when Th1 expression decreases, the bacterial load will increase with increasing Th2 (which is assumed not to be protective). Increasing bacteria results in more infected macrophages hence increased CFU shedding.

Bottom Line: The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type).We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011).In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, 37996-1527, United States of America.

ABSTRACT
Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular bacterial pathogen that causes Johne's disease (JD) in cattle and other animals. The hallmark of MAP infection in the early stages is a strong protective cell-mediated immune response (Th1-type), characterized by antigen-specific γ-interferon (IFN-γ). The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type). Interleukin-10 (IL-10) is believed to play a critical role in the regulation of host immune responses to MAP infection and potentially orchestrate the reversal of Th1/Th2 immune dominance during disease progression. However, how its role correlates with MAP infection remains to be completely deciphered. We developed mathematical models to explain probable mechanisms for IL-10 involvement in MAP infection. We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011). Our models predicted that IL-10 can have different roles during MAP infection, (i) it can suppress the Th1 expression, (ii) can enhance Th2 (IL-4) expression, and (iii) can suppress the Th1 expression in synergy with IL-4. In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP. We also predicted that Th1-mediated responses (IFN-γ) can lead to high expression of IL-10 and that infection burden regulates Th2 suppression by the Th1 response. Our models highlight areas where more experimental data is required to refine our model assumptions, and further test and investigate the role of IL-10 in MAP infection.

Show MeSH
Related in: MedlinePlus