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Characterization of the inflammatory phenotype of Mycobacterium avium subspecies paratuberculosis

ABSTRACT: Understanding the pathogenic mechanisms and host responses to Johne's disease, caused by Mycboacterium avium subspecies paratuberculosis (MAP), is complicated by a number of challenges of the disease progression and lack of ex vivo models to study the disease. We describe novel cell culture passage model which mimics the course of infection in vivo. Using this model we determined that cell culture passaged MAP develops an inflammatory phenotype initiating higher levels of pro-inflammatory cytokines and chemokines compared to levels initiated by non-passaged MAP. To verify that the MAP phenotypes were changing, we conducted transcriptome analysis of each population during the passage model and identified a change in gene expression, specifically and upregulation of genes involved in the biosynthesis of lipid components within the cell. Lipidomic analysis showed dramatically different lipid profiles between the 2 populations. These transcriptome changes were validated by the identification of high levels of upregulated transcripts from MAP-infected cattle ileal tissue. In total, this study described a novel model used to show that MAP changes phenotype during intracellular passage, thus changing its lipid profile and triggering an inflammatory response in the host leading to the severe clinical phage of Johne's disease.

ORGANISM(S): Mycobacterium avium subsp. avium Mycobacterium avium subsp. paratuberculosis

PROVIDER: GSE62566 | GEO | 2014/11/01

SECONDARY ACCESSION(S): PRJNA264417

REPOSITORIES: GEO

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Project description:Johne’s disease is a chronic, incurable and fatal enteric infection of ruminant species caused by Mycobacterium avium subspecies paratuberulosis (MAP) and responsible in hundreds of millions of dollars in losses for the agricultural industry. Natural infection usually begins with bacterial uptake and translocation through the epithelium of the small intestine, followed by ingestion by tissue macrophages and dissemination via the lymphatic or blood system throughout the body. To gain insights into the host innate immune responses, promoting an intracellular phenotype and adaptation of MAP within phagocytic cells, we utilized the previously developed cell culture passage model and the mass spectrometric-based quantitative proteomics approach. Using the cell culture system, which mimics an in vivo interaction of MAP with intestinal epithelium and tissue macrophages, bacteria were passed through the bovine epithelial cells and, subsequently, used for macrophage infection (termed indirect infection), while uninfected cells and macrophage infection initiated with the culture grown bacteria (termed direct infection) served as controls. Approximately 3,900 proteins were identified across all studied groups. The comparison within the subset of proteins that showed synthesis for more than two-fold in the direct infection over the uninfected control revealed an enrichment for the pro-inflammatory pathways such as the NF-κB and cytokine/chemokine signaling, positive regulation of defense response, cell activation involved in the immune response and adaptive immune system. While these responses were absent in the indirect infection, cellular pathways such as cell cycle, healing, regulation of cell adhesion, ensemble of core extracellular matrix proteins, cell surface integrins and proteins mediating the integrin signaling were remarkably high within the indirect infection. In addition to the global analysis of the macrophage proteome, in this study, we validate the proteomics data and confirm our hypothesis that MAP passage through epithelial cells can alter the way in which bacteria are able to modulate the expression and signaling of integrins in phagocytes. We demonstrate that predominant expression of integrins in the indirectly infected macrophages allows phagocytic cells to initiate stronger binding and efficient translocation through the endothelial cells, suggesting the important role of integrins in the spread of MAP infection.

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Characterization of the inflammatory phenotype of Mycobacterium avium subspecies paratuberculosis

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