Abstract
Johne’s disease (JD) caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a chronic, wasting infectious disease in ruminants that causes enormous economic losses to the dairy and beef cattle industries. Understanding the mechanism of persistency of MAP is key to produce novel ideas for the development of new diagnostic methods or prevention techniques. We sought interactions between the host and MAP using epithelial passage model, which mimic initial stage of infection. From the transcriptomic analysis of bovine immune cells (PBMCs), it was suggested that infection through the epithelial cells elicited prolonged Th17-derived immune response, as indicated by upregulation of IL-17A, IL-17F and RORC until 120 h p.i., compared to directly infected PBMCs. Global downregulation of gene expression was observed after 72 h p.i., especially for genes encoding cell surface receptors of phagocytic cells, such as Toll-like receptors and MHC class II molecules. In addition, the cholesterol efflux transporters ABCA1, ABCG1, and APOE, which are regulated by the LXR/RXR pathway, were downregulated. In summary, it would be suggested that the host initiate immune response to activate Th17-derived cytokines, and MAP survives persistently by altering the host adaptive immune response by suppressing surface receptors and manipulating lipid metabolism in phagocytic cells.
Highlights
Johne’s disease (JD) caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a chronic, wasting infectious disease in ruminants that causes enormous economic losses to the dairy and beef cattle industries
In vivo studies could not elucidate the initial stage of infection related to persistence, such as the immune response to the formation of granuloma, and in vitro studies could not represent the actual course of infection because the infection models were mainly based on single cell types, such as monocyte-derived macrophages (MDMs)
Specific amplification for sigA, the housekeeping gene of MAP, was observed in both Madin–Darby bovine kidney (MDBK) and peripheral blood mononuclear cells (PBMCs) at all time points, while only non-specific amplification was observed in the non-infection control (Fig. S1)
Summary
Johne’s disease (JD) caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a chronic, wasting infectious disease in ruminants that causes enormous economic losses to the dairy and beef cattle industries. The detection sensitivity of these methods is low because fecal shedding occurs in an intermittent manner, and antibody levels against MAP in serum rise during a relatively later stage of infection[4,5] This diagnostic difficulty is due to the nature of MAP infection. In vivo studies could not elucidate the initial stage of infection related to persistence, such as the immune response to the formation of granuloma, and in vitro studies could not represent the actual course of infection because the infection models were mainly based on single cell types, such as monocyte-derived macrophages (MDMs). To understand the exact response of immune cells against MAP infection during the initial stage of infection, we designed an epithelial passage model to mimic the course of infection in an in vitro environment. The aim of the study was to identify pathogenic pathways by comparison of the expression of cytokines and global genes of bovine peripheral blood mononuclear cells (PBMCs) in the context of MAP infection with or without epithelial processing
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