Abstract
Two different forms of clinical paratuberculosis in sheep are recognised, related to the level of bacterial colonization. Paucibacillary lesions are largely composed of lymphocytes with few bacteria, and multibacillary pathology is characterized by heavily-infected macrophages. Analysis of cytokine transcripts has shown that inflammatory Th1/Th17 T cells are associated with development of paucibacillary pathology and Th2 cytokines are correlated with multibacillary disease. The master regulator T cell transcription factors TBX21, GATA3, RORC2 and RORA are critical for the development of these T cell subsets. Sequence variations of the transcription factors have also been implicated in the distinct disease forms of human mycobacterial and gastrointestinal inflammatory diseases. Relative RT-qPCR was used to compare expression levels of each transcript variant of the master regulators in the ileo-caecal lymph nodes of uninfected controls and sheep with defined paucibacillary and multibacillary pathology. Low levels of GATA3 in multibacillary sheep failed to confirm that multibacillary paratuberculosis is caused simply by a Th2 immune response. However, high levels of TBX21, RORC2 and RORC2v1 highlights the role of Th1 and Th17 activation in paucibacillary disease. Increased RORAv1 levels in paucibacillary tissue suggests a role for RORα in Th17 development in sheep; while elevated levels of RORAv4 hints that this variant might inhibit RORα function and depress Th17 development in multibacillary sheep.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-016-0368-3) contains supplementary material, which is available to authorized users.
Highlights
Paratuberculosis (Johne’s disease) is a common intestinal disease of ruminants caused by infection with the intracellular bacterium Mycobacterium avium subspecies paratuberculosis (Map) [1]
Previous studies investigating cytokine transcripts indicated that sheep paucibacillary disease is strongly associated with Th1/Th17 activation and that multibacillary pathology is linked to a Th2 T cell response [7, 34, 35]
Tbx21, GATA-3, RORγt and RORα are the master regulator transcription factors responsible for controlling the polarization of these T cell subsets; and splice variants of these genes have been described in sheep, some of which are differentially expressed in gastrointestinal parasitic disease [31]
Summary
Paratuberculosis (Johne’s disease) is a common intestinal disease of ruminants caused by infection with the intracellular bacterium Mycobacterium avium subspecies paratuberculosis (Map) [1]. About 70% of the diseased animals develop multibacillary or lepromatous pathology with lesions in the terminal ileum composed of heavily infected macrophages [3, 4], and the remainder develop paucibacillary or tuberculoid. The immunology of paratuberculosis in sheep is similar to that of the tuberculoid and lepromatous forms of tuberculosis and leprosy [5, 6]. The immune response associated with the two forms of the disease is not a simple matter of Th1/Th2 discrimination as there seems to be a total T cell dysfunction and loss of homeostasis in animals with multibacillary pathology [11,12,13], possibly concerned with changes to co-stimulatory and second messenger expression [14, 15].
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