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Title:   Author  item
                                            Thacker, Tyleritem
                                            Palmer, Mitchellitem
                                            Waters, Wade
  Submitted to: Veterinary Immunology and Immunopathology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 5/15/2007
                                    Publication  Date: 10/15/2007
                                    Citation: Thacker, T.C., Palmer, M.V., Waters, W.R. 2007. Associations Between Cytokine Gene Expression and Pathology in Mycobacterium bovis Infected Cattle. Veterinary Immunology and Immunopathology. 119(3-4):204-213.Interpretive Summary: Mycobacterium bovis causes tuberculosis in mammalian species including cattle and humans. In the US, infected white-tailed deer are a reservoir of infection that threatens cattle in endemic areas. This continued threat to herd health emphasizes the need for the development of an effective vaccine to protect cattle in these areas. A significant impediment to the development of a vaccine is the lack of knowledge about effective immune responses. To begin to evaluate effective immune responses, cytokine gene expression in responses to M. bovis infection was evaluated in uninfectected and infected cattle. Cytokine gene expression was evaluated in stimulated peripheral blood lymphocytes and in tissues obtained at necropsy. Infected animals expressed more Interferon-gamma (IFN-g), Tumor Necrosis Factor-alpha, Inducible Nitrous Oxide Synthase (iNOS), Interleukin-4 and Interleukin-5 than did the uninfected controls. Animals with greater pathology, and thus more likely to shed infectious bacteria, had more robust immune responses early after infection. In addition, these early immune responses correlated with development of pathology. Infected tissues also expressed IFN-g and iNOS. These data demonstrate that immune responses to M. bovis that occur immediately after infection may establish the final outcome of disease. Furthermore, insights into these early events may be necessary to development of effective vaccines against M. bovis.
                                Technical Abstract: Mycobacterium bovis infection results in the development of tuberculosis in many mammalian species including humans. In the US, infected white-tailed deer (WTD) represent a reservoir of infection that threatens cattle in endemic areas. This continued threat to herd health emphasizes the need for the development of an effective vaccine to protect cattle in these areas. A significant impediment to vaccine development has been the lack of clear immune correlates of protective immunity. To begin to discover correlates of immunity, cytokine gene expression in response to M. bovis infection was evaluated. Ten Holstein calves were infected using the intratonsilar inoculation. Five uninfected animals served as controls. At various time points after infection peripheral blood leukocytes (PBL) were isolated and stimulated with either purified protein derivative of M. bovis (PPD), a recombinant fusion protein comprised of ESAT6 and CFP10 (rESAT6:CFP10), or PBS. After 16 hours of stimulation total RNA was isolated and gene expression evaluated using reverse-transcriptase real-time PCR. Pathology was evaluated at the conclusion of the experiment. Expression of IFN-g, TNF-a, iNOS and IL-4 increased in response to infection, whereas, IL-10 expression decreased. Difference in expression between the infected and uninfected animals was greatest early after infection. Infected animals were divided into two groups based on pathology. Lesions were primarily found in the lymph nodes of the head in the low pathology group, whereas, animals in the high pathology group also had lesions in the lungs and lung associated lymph nodes. Gene expression was compared between animals in the high and low pathology groups to evaluate associations between pathology and gene expression. Animals in the high pathology group expressed more IFN-g, TNF a, iNOS and IL-4 than did animals in the low pathology group at early time points. Expression of these cytokines correlated with pathology 30 days p.i. Correlation decreased as infection progressed. Expression of IL-10 decreased over time in PBLs from animals in the high pathology group. At 85 days p.i. animals in the high pathology group expressed 2-fold less RNA than did animals in the low pathology group and the uninfected controls. Expression of IL-10 inversely correlated with pathology (r=-0.71, p=0.001). Expression of IFN-gamma and iNOS was significantly greater in tissues adjacent to lesions from infected animals compared to tissues from uninfected animals. Animals in the high pathology group appear to have more robust immune responses early after infection and these robust responses may contribute to pathology.


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