7 research outputs found

    Regulatory T cell activity and signs of T cell unresponsiveness in bovine paratuberculosis

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    Johne’s disease, caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP), is a wasting disease of ruminants displaying a long subclinical stage of infection followed by clinical disease characterized by severe diarrhea, wasting, and premature death. Immunologically, subclinical disease is characterized by a Th1 response effective at controlling intracellular infections such as that caused by MAP. In late subclinical disease, the Th1 response subsides and a non-protective Th2 response becomes prominent. One hypothesis for this shift in immune paradigm is that a population of MAP-reactive regulatory T cells (Tregs) develops during subclinical infection, limiting Th1-type responses to MAP antigens. To investigate this we sought to accomplish the following: 1) Determine if CD4+CD25- T cells exposed to MAP-infected macrophages develop a Treg phenotype, 2) Develop a method to expand the relative abundance of Tregs in bovine peripheral blood lymphocyte populations, and 3) Identify functional activities of expanded Tregs when combined with autologous peripheral blood mononuclear cells (PBMCs) and live MAP. We found that CD4+CD25- T cells exposed to MAP-infected macrophages from cows with Johne’s disease do not show signs of a Treg phenotype and appear unresponsive to MAP antigens. A method for Treg expansion was successfully developed; however, based on results obtained in the subsequent functional studies it appears that these Tregs are not MAP-specific. Overall, it seems that T cell unresponsiveness, rather than Treg activity, is driving the Th1-to-Th2 immune shift observed during Johne’s disease. Further, we have successfully developed a method to enrich non-specific bovine Tregs that exert suppressive effects against Th1 cytokine production

    Characterization of the inflammatory phenotype of Mycobacterium avium subspecies paratuberculosis using a novel cell culture passage model

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    Understanding the pathogenic mechanisms of Mycobacterium avium subspecies paratuberculosis (MAP) and the host responses to Johne’s disease is complicated by the multi-faceted disease progression, late-onset host reaction and the lack of available ex vivo infection models. We describe a novel cell culture passage model that mimics the course of infection in vivo. The developed model simulates the interaction of MAP with the intestinal epithelial cells, followed by infection of macrophages and return to the intestinal epithelium. MAP internalization triggers a minimal inflammatory response. After passage through a macrophage phase, bacterial reinfection of MDBK epithelial cells, representing the late phase of intestinal mucosal infection, is associated with increased synthesis of the pro-inflammatory transcripts of IL-6, CCL5, IL-8 and IL-18, paired with decreased levels of TGFb. Transcriptome analysis of MAP from each stage of epithelial cell infection identified increased expression of lipid biosynthesis and lipopeptide modification genes in the inflammatory phenotype of MAP. Total lipid analysis by HPLC-ES/MS indicates different lipidomic profiles between the two phenotypes and a unique set of lipids composing the inflammatory MAP phenotype. The presence of selected upregulated lipid-modification gene transcripts in samples of ileal tissue from cows diagnosed with Johne’s disease supports and validates the model. By using the relatively simple cell culture passage model, we show that MAP alters its lipid composition during intracellular infection and acquires a pro-inflammatory phenotype, which likely is associated with the inflammatory phase of Johne’s disease

    Immunoregulation in Fungal Diseases

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    This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte-associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi
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