|MAGOMBEDZE, GESHAM - University Of Tennessee|
|EDA, SHIGETOSHI - University Of Tennessee|
Submitted to: PLoS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2015
Publication Date: 11/30/2013
Citation: Magombedze, G., Eda, S., Stabel, J.R. 2013. Predicting the role of IL-10 in the regulation of the adaptive immune responses in Mycobacterium avium subsp. paratuberculosis infections using mathematical models. PLoS One. 10(11):e0141539. doi: 10.1371/journal.pone.0141539.
Interpretive Summary: Johne's disease is a chronic, debilitating intestinal disorder in cattle characterized by diarrhea, reduced feed intake, weight loss and death. Cattle usually become infected as young calves by ingesting feces containing the causative bacteria. However, symptoms of disease do not usually present themselves until the animals reach 3 to 5 years of age or even older. During this time the animal is infected and may be shedding the organism in its feces without showing any clinical signs of disease. In addition to reduced milk production by these animals, they also present a potential infective threat to the rest of the herd. Host immune responses to Johne’s disease are dynamic and change during the progression of disease from a latent, asymptomatic stage to a more advanced stage demonstrating symptoms listed above. Modeling the immune responses of the host during infection will help us understand how the disease progresses. This paper develops a model to explain the dynamics of the infection process in young calves and how key proteins secreted during infection may modulate the immune response. Understanding the host immune response to this pathogen will help us develop control measures to prevent the spread of infection.
Technical Abstract: Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular bacterial pathogen that causes Johne’s disease in cattle and other animals. Infection follows ingestion of the bacteria primarily through the fecal oral route and results in the colonization of the intestine and a granulomatous enteric inflammation. The hallmark of MAP infection in the early stages is a strong protective cell-mediated immune response (Th1-type), characterized by antigen-specific gamma-interferon (IFN-gamma). The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type), with concomitant increases in MAP fecal shedding. 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. How IL-10 regulates the Th1 and Th2 immune responses, and how its role correlates with MAP infection remains to be completely deciphered. We developed and used mathematical models to explain probable mechanisms for IL-10 involvement in MAP infection and how these mechanisms describe MAP disease and immune kinetics. We tested our models with IL-4, IL-10, IFN-gamma, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days. 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-gamma) can lead to high expression of IL-10 and that infection burden regulates/manipulates 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. Based upon these results we have proposed several experiments that can be carried out to further validate our prediction.