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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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Model fitting and predicted immune interaction pathways.A) Shows how the predicted pathways represented by interaction maps/diagrams in B reproduce the experimental data. Best fits for calves A (A.1), B (B.1) and C (C.1) were obtained with models with immune interactions represented by signaling pathways A.2, B.2 and C.2 in B, respectively. The models used to predict these signaling pathways/maps are given in the supporting information file S1 Text, systems of equations (S1), (S2), and (S3), respectively. The first observed experimental values of each variable were used as the initial condition. The estimated parameters are given in Table 1 and they show the importance of these interactions. The magnitude of the estimated parameter indicates the strength of the interaction, while the 95%CIs show the uncertainty in the parameter estimates. The shaded regions represent the uncertainty in the model simulation results. B) Show the predicted biological interactions between IL-10, IFN-γ, and IL-4 that explain the immune kinetics and the CFU shedding dynamics of all the calves. Arrowed lines represent stimulated, dashed arrowed lines represent an enhancement of an effect, lines with a flat end represent the inhibition/suppression, and arrowed semi-circles represent proliferation/expansion. The dotted arrowed lines that start with a solid circle represent an indirect and implied stimulation that was predicted not to be essential to explain the data for some animals included to indicate that an infection is required for the initial cytokine stimulation but may not be important for their continued expression.
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pone.0141539.g002: Model fitting and predicted immune interaction pathways.A) Shows how the predicted pathways represented by interaction maps/diagrams in B reproduce the experimental data. Best fits for calves A (A.1), B (B.1) and C (C.1) were obtained with models with immune interactions represented by signaling pathways A.2, B.2 and C.2 in B, respectively. The models used to predict these signaling pathways/maps are given in the supporting information file S1 Text, systems of equations (S1), (S2), and (S3), respectively. The first observed experimental values of each variable were used as the initial condition. The estimated parameters are given in Table 1 and they show the importance of these interactions. The magnitude of the estimated parameter indicates the strength of the interaction, while the 95%CIs show the uncertainty in the parameter estimates. The shaded regions represent the uncertainty in the model simulation results. B) Show the predicted biological interactions between IL-10, IFN-γ, and IL-4 that explain the immune kinetics and the CFU shedding dynamics of all the calves. Arrowed lines represent stimulated, dashed arrowed lines represent an enhancement of an effect, lines with a flat end represent the inhibition/suppression, and arrowed semi-circles represent proliferation/expansion. The dotted arrowed lines that start with a solid circle represent an indirect and implied stimulation that was predicted not to be essential to explain the data for some animals included to indicate that an infection is required for the initial cytokine stimulation but may not be important for their continued expression.

Mentions: Parameters shown were those that were varied during fitting between the models. Dash (-) means a parameter was fixed during fitting and they have the same values between the models, that is hi (i = 1 − 2) = 10.0, Ai (i = 1 − 3) αi(i = 1 − 4) = 0.0033, βi(i = 1 − 4) = 0.015, γi(i = 1 − 2) = 0.015. The system of equations/models (S1), (S2) and (S3) in S1 Text were used to generate the fits (Fig 2) and in estimating the parameters. Priors for α’s and β’s were set between 0–1, while for hi’s between 0–10.


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)

Model fitting and predicted immune interaction pathways.A) Shows how the predicted pathways represented by interaction maps/diagrams in B reproduce the experimental data. Best fits for calves A (A.1), B (B.1) and C (C.1) were obtained with models with immune interactions represented by signaling pathways A.2, B.2 and C.2 in B, respectively. The models used to predict these signaling pathways/maps are given in the supporting information file S1 Text, systems of equations (S1), (S2), and (S3), respectively. The first observed experimental values of each variable were used as the initial condition. The estimated parameters are given in Table 1 and they show the importance of these interactions. The magnitude of the estimated parameter indicates the strength of the interaction, while the 95%CIs show the uncertainty in the parameter estimates. The shaded regions represent the uncertainty in the model simulation results. B) Show the predicted biological interactions between IL-10, IFN-γ, and IL-4 that explain the immune kinetics and the CFU shedding dynamics of all the calves. Arrowed lines represent stimulated, dashed arrowed lines represent an enhancement of an effect, lines with a flat end represent the inhibition/suppression, and arrowed semi-circles represent proliferation/expansion. The dotted arrowed lines that start with a solid circle represent an indirect and implied stimulation that was predicted not to be essential to explain the data for some animals included to indicate that an infection is required for the initial cytokine stimulation but may not be important for their continued expression.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0141539.g002: Model fitting and predicted immune interaction pathways.A) Shows how the predicted pathways represented by interaction maps/diagrams in B reproduce the experimental data. Best fits for calves A (A.1), B (B.1) and C (C.1) were obtained with models with immune interactions represented by signaling pathways A.2, B.2 and C.2 in B, respectively. The models used to predict these signaling pathways/maps are given in the supporting information file S1 Text, systems of equations (S1), (S2), and (S3), respectively. The first observed experimental values of each variable were used as the initial condition. The estimated parameters are given in Table 1 and they show the importance of these interactions. The magnitude of the estimated parameter indicates the strength of the interaction, while the 95%CIs show the uncertainty in the parameter estimates. The shaded regions represent the uncertainty in the model simulation results. B) Show the predicted biological interactions between IL-10, IFN-γ, and IL-4 that explain the immune kinetics and the CFU shedding dynamics of all the calves. Arrowed lines represent stimulated, dashed arrowed lines represent an enhancement of an effect, lines with a flat end represent the inhibition/suppression, and arrowed semi-circles represent proliferation/expansion. The dotted arrowed lines that start with a solid circle represent an indirect and implied stimulation that was predicted not to be essential to explain the data for some animals included to indicate that an infection is required for the initial cytokine stimulation but may not be important for their continued expression.
Mentions: Parameters shown were those that were varied during fitting between the models. Dash (-) means a parameter was fixed during fitting and they have the same values between the models, that is hi (i = 1 − 2) = 10.0, Ai (i = 1 − 3) αi(i = 1 − 4) = 0.0033, βi(i = 1 − 4) = 0.015, γi(i = 1 − 2) = 0.015. The system of equations/models (S1), (S2) and (S3) in S1 Text were used to generate the fits (Fig 2) and in estimating the parameters. Priors for α’s and β’s were set between 0–1, while for hi’s between 0–10.

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