title: Predicting the Role of IL-10 in the Regulation of the Adaptive Immune Responses in Mycobacterium avium Subsp. paratuberculosis Infections Using Mathematical Models.
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.
authors.affiliation: National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, 37996-1527, United States of America.|MRC Centre for Outbreak Analysis & Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.
authors.forename: Gesham
authors.initials: G
authors.lastname: Magombedze
authors.affiliation: Department of Forestry, Wildlife, and Fisheries, University of Tennessee, Knoxville, Tennessee, 37996-1527, United States of America.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Eda
authors.affiliation: USDA-ARS, National Animal Disease, Ames, Iowa, 50010, United States of America.
authors.forename: Judy
authors.initials: J
authors.lastname: Stabel
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002417:Cattle; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008962:Models, Theoretical; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology*; D010283:Paratuberculosis / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma