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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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Related in: MedlinePlus

Model cartoons.A) A cytokine signaling model diagram. IFN-γ, IL-4, IL-10 are assumed to interact together and in-turn influence immune responses and these potentially affect MAP CFU shedding. The model assumes that IL-10 can take multiple functions for instance, they can be assumed to enhance IL-4 production or can be assumed to inhibit IFN-γ production. Further production of IL-10 can be assumed to be positively correlated with the amount of CFUs. Also, the amount of excreted CFUs can be correlated with the expressed Th1 and Th2 responses and as well as by IL-10. Arrowed lines represent stimulation, lines with a flat end represent suppression/inhibition. Broken arrowed lines represent probable mechanisms without clear support from biological evidence that may represent a probable inhibition or stimulation. B) A cell compartmental model diagram. Macrophages remove/kill free bacteria at rate km and get infected at rate ki giving rise to infected macrophages. Uninfected and infected macrophages have death rates μm and μi, respectively. Infected macrophages burst at rate kb and they release No bacteria at the same time. A Th1 response is assumed to kill infected macrophages at rate kl. IFN-γ and IL-4 are assumed to be Th1 and Th2 surrogates. Treg cells are assumed to produce IL-10 and this is captured indirectly through the population of infected macrophages. IL-10 is assumed to either enhance IL-4 production or suppress IFN-γ production. Both the population of infected macrophages and free bacteria are assumed to be the source of bacteria excreted in feces at rates λ1 and λ2, respectively.
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pone.0141539.g001: Model cartoons.A) A cytokine signaling model diagram. IFN-γ, IL-4, IL-10 are assumed to interact together and in-turn influence immune responses and these potentially affect MAP CFU shedding. The model assumes that IL-10 can take multiple functions for instance, they can be assumed to enhance IL-4 production or can be assumed to inhibit IFN-γ production. Further production of IL-10 can be assumed to be positively correlated with the amount of CFUs. Also, the amount of excreted CFUs can be correlated with the expressed Th1 and Th2 responses and as well as by IL-10. Arrowed lines represent stimulation, lines with a flat end represent suppression/inhibition. Broken arrowed lines represent probable mechanisms without clear support from biological evidence that may represent a probable inhibition or stimulation. B) A cell compartmental model diagram. Macrophages remove/kill free bacteria at rate km and get infected at rate ki giving rise to infected macrophages. Uninfected and infected macrophages have death rates μm and μi, respectively. Infected macrophages burst at rate kb and they release No bacteria at the same time. A Th1 response is assumed to kill infected macrophages at rate kl. IFN-γ and IL-4 are assumed to be Th1 and Th2 surrogates. Treg cells are assumed to produce IL-10 and this is captured indirectly through the population of infected macrophages. IL-10 is assumed to either enhance IL-4 production or suppress IFN-γ production. Both the population of infected macrophages and free bacteria are assumed to be the source of bacteria excreted in feces at rates λ1 and λ2, respectively.

Mentions: We developed and implemented two different modelling frameworks to closely examine and understand the experimental data. First, we developed a cytokine signalling model to analyse and predict the interactions between the measured variables, the cytokines IFN-γ, IL-4, IL-10 and how these correlate with CFU/ bacteria patterns in the excreted faeces (Fig 1A). We use the model to explore how IL-10 regulates the expression of IFN-γ and IL-4 and in turn how CFU shedding is altered. Second, we developed a model that realises cell interactions within the host and bacteria outside the host (in the excreted faeces). The model then links the within host compartment and the outside of host compartment (Fig 1B). This model is centred on the assumption that the cytokines, IFN-γ and IL-4 (measured in the experiment) are strong correlates (or surrogates) for Th1 and Th2 immune responses [8, 23–25]. The CFU measurements are taken as the cultivated (cultured) population of MAP bacteria from the gut excrement. The model is then used to investigate how IL-10 regulates the Th1 and Th2 responses and how this translates to the observed CFU shedding kinetics.


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 cartoons.A) A cytokine signaling model diagram. IFN-γ, IL-4, IL-10 are assumed to interact together and in-turn influence immune responses and these potentially affect MAP CFU shedding. The model assumes that IL-10 can take multiple functions for instance, they can be assumed to enhance IL-4 production or can be assumed to inhibit IFN-γ production. Further production of IL-10 can be assumed to be positively correlated with the amount of CFUs. Also, the amount of excreted CFUs can be correlated with the expressed Th1 and Th2 responses and as well as by IL-10. Arrowed lines represent stimulation, lines with a flat end represent suppression/inhibition. Broken arrowed lines represent probable mechanisms without clear support from biological evidence that may represent a probable inhibition or stimulation. B) A cell compartmental model diagram. Macrophages remove/kill free bacteria at rate km and get infected at rate ki giving rise to infected macrophages. Uninfected and infected macrophages have death rates μm and μi, respectively. Infected macrophages burst at rate kb and they release No bacteria at the same time. A Th1 response is assumed to kill infected macrophages at rate kl. IFN-γ and IL-4 are assumed to be Th1 and Th2 surrogates. Treg cells are assumed to produce IL-10 and this is captured indirectly through the population of infected macrophages. IL-10 is assumed to either enhance IL-4 production or suppress IFN-γ production. Both the population of infected macrophages and free bacteria are assumed to be the source of bacteria excreted in feces at rates λ1 and λ2, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0141539.g001: Model cartoons.A) A cytokine signaling model diagram. IFN-γ, IL-4, IL-10 are assumed to interact together and in-turn influence immune responses and these potentially affect MAP CFU shedding. The model assumes that IL-10 can take multiple functions for instance, they can be assumed to enhance IL-4 production or can be assumed to inhibit IFN-γ production. Further production of IL-10 can be assumed to be positively correlated with the amount of CFUs. Also, the amount of excreted CFUs can be correlated with the expressed Th1 and Th2 responses and as well as by IL-10. Arrowed lines represent stimulation, lines with a flat end represent suppression/inhibition. Broken arrowed lines represent probable mechanisms without clear support from biological evidence that may represent a probable inhibition or stimulation. B) A cell compartmental model diagram. Macrophages remove/kill free bacteria at rate km and get infected at rate ki giving rise to infected macrophages. Uninfected and infected macrophages have death rates μm and μi, respectively. Infected macrophages burst at rate kb and they release No bacteria at the same time. A Th1 response is assumed to kill infected macrophages at rate kl. IFN-γ and IL-4 are assumed to be Th1 and Th2 surrogates. Treg cells are assumed to produce IL-10 and this is captured indirectly through the population of infected macrophages. IL-10 is assumed to either enhance IL-4 production or suppress IFN-γ production. Both the population of infected macrophages and free bacteria are assumed to be the source of bacteria excreted in feces at rates λ1 and λ2, respectively.
Mentions: We developed and implemented two different modelling frameworks to closely examine and understand the experimental data. First, we developed a cytokine signalling model to analyse and predict the interactions between the measured variables, the cytokines IFN-γ, IL-4, IL-10 and how these correlate with CFU/ bacteria patterns in the excreted faeces (Fig 1A). We use the model to explore how IL-10 regulates the expression of IFN-γ and IL-4 and in turn how CFU shedding is altered. Second, we developed a model that realises cell interactions within the host and bacteria outside the host (in the excreted faeces). The model then links the within host compartment and the outside of host compartment (Fig 1B). This model is centred on the assumption that the cytokines, IFN-γ and IL-4 (measured in the experiment) are strong correlates (or surrogates) for Th1 and Th2 immune responses [8, 23–25]. The CFU measurements are taken as the cultivated (cultured) population of MAP bacteria from the gut excrement. The model is then used to investigate how IL-10 regulates the Th1 and Th2 responses and how this translates to the observed CFU shedding kinetics.

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