GENOMIC AND IMMUNOLOGICAL CHARACTERISTICS OF JOHNE'S DISEASE
Location: Infectious Bacterial Diseases Research Unit
Title: Primary transcriptomes of Mycobacterium avium subsp. paratuberculosis reveal proprietary pathways in tissue and macrophages
| Janagama, Harish - |
| Lamont, Elise - |
| George, Sajan - |
| Xu, Wayne - |
| Tu, Zheng - |
| Wells, Scott - |
| Schefers, Jeremy - |
| Sreevatsan, Srinand - |
Submitted to: Biomed Central (BMC) Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 20, 2010
Publication Date: October 12, 2010
Citation: Janagama, H.K., Lamont, E.A., George, S., Bannantine, J.P., Xu, W., Tu, Z.J., Wells, S.J., Schefers, J., Sreevatsan, S. 2010. Primary transcriptomes of Mycobacterium avium subsp. paratuberculosis reveal proprietary pathways in tissue and macrophages. Biomed Central (BMC) Genomics. 11(1):561.
Interpretive Summary: The question of how the bacterium called Mycobacterium avium subspecies paratuberculosis can cause Johne’s disease remains largely unanswered. One major reason for this knowledge gap is that the organism is difficult to work with. In this paper we attempt to bring some clarity to this question by examining the all genes that the bacterium expresses while inside tissues and cells. These locations are where you would normally find the bacterium in the infected cattle. The data yielded the first list of genes we know the bacterium uses to survive inside the cow. This is important because we now have some clues about what the genes are that cause the disease. This paper is of primary interest to scientists who will build on this information to prevent infection and subsequent disease.
Background: Mycobacterium avium subsp. paratuberculosis persistently infect intestines and mesenteric lymph nodes leading to a prolonged subclinical disease. We investigated the intracellular lifestyle of MAP in the intestines and lymph nodes to understand the MAP pathways that function to govern this persistence. While the current trend in MAP research is to analyze regulated gene sets utilizing defined, in vitro stress related or advanced surgical methods with various animal species, we have uncovered common and unique MAP pathways in naturally infected cow intestines and lymph nodes.
Results: Our transcriptional analysis suggests that about 21%, 8% and 3% of the entire MAP genome was represented either inside tissues, macrophages or both, respectively. Genes were classified into various functional categories based on clusters of orthologous groups (COGs). The functional categories enriched in the tissues include genes involved in transcription, lipid metabolism, energy production, inorganic ion transport and unknown function.
DNA replication and repair, cell wall biogenesis, secondary metabolite synthesis and transport, intracellular trafficking and secretion were enriched specifically inside macrophages. Whereas shared gene expression between natural infection and in vitro macrophage infection was that of transcription and inorganic ion transport and metabolism. We identified that in macrophage infection, MAP upregulates expression (fold change >2.0, P<0.05) of genes belonging to MAP specific genomic insertions (defined earlier as LSP 2, 4, 11, 12, 14, 15 and 16). We also evidenced an upregulation of genes belonging to ³deletion 1 and 2², earlier described as genomic insertions specific for cattle strains of MAP. Additionally, located within the MAP specific pathogenicity island LSP15 is MAP3773c, a possible Ferric Uptake Regulator (FUR) which was downregulated and located within LSP14 and immediately downstream of a putative FUR binding DNA region is an ABC transporter operon (MAP3731c - MAP3736c) and a putative siderophore biosynthesis operon (MAP3740 - MAP3746) which were upregulated.
Conclusion: Regulatory pathways that govern the lifecycle of MAP appear to be specified by tissue and cell type. While tissues show a ³shut-down² of major MAP metabolic genes, infected macrophages upregulate the MAP specific pathogenicity island responsible for iron acquisition. Many of these regulatory pathways rely on the advanced interplay of host and pathogen and in order to decipher their message, an interactome must be established using a systems biology approach. Identified MAP pathways place current research into direct alignment to meeting the future challenge of creating a MAP-host interactome.