Systems Biology Analysis of Gene Expression during In Vivo Mycobacterium avium paratuberculosis Enteric Colonization Reveals Role for Immune Tolerance

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dc.contributorVirginia Techen
dc.contributor.authorKhare, Sangeetaen
dc.contributor.authorLawhon, Sara D.en
dc.contributor.authorDrake, Kenneth L.en
dc.contributor.authorNunes, Jairo E. S.en
dc.contributor.authorFigueiredo, Josely F.en
dc.contributor.authorRossetti, Carlos A.en
dc.contributor.authorGull, Tamaraen
dc.contributor.authorEverts, Robin E.en
dc.contributor.authorLewin, Harris A.en
dc.contributor.authorGalindo, Cristi L.en
dc.contributor.authorGarner, Harold R.en
dc.contributor.authorAdams, Leslie Garryen
dc.date.accessed2014-05-01en
dc.date.accessioned2014-06-17T20:12:08Zen
dc.date.available2014-06-17T20:12:08Zen
dc.date.issued2012-08-17en
dc.description.abstractSurvival and persistence of Mycobacterium avium subsp. paratuberculosis (MAP) in the intestinal mucosa is associated with host immune tolerance. However, the initial events during MAP interaction with its host that lead to pathogen survival, granulomatous inflammation, and clinical disease progression are poorly defined. We hypothesize that immune tolerance is initiated upon initial contact of MAP with the intestinal Peyer's patch. To test our hypothesis, ligated ileal loops in neonatal calves were infected with MAP. Intestinal tissue RNAs were collected (0.5, 1, 2, 4, 8 and 12 hrs post-infection), processed, and hybridized to bovine gene expression microarrays. By comparing the gene transcription responses of calves infected with the MAP, informative complex patterns of expression were clearly visible. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis, and genes were grouped into the specific pathways and gene ontology categories to create a holistic model. This model revealed three different phases of responses: i) early (30 min and 1 hr post-infection), ii) intermediate (2, 4 and 8 hrs post-infection), and iii) late (12 hrs post-infection). We describe here the data that include expression profiles for perturbed pathways, as well as, mechanistic genes (genes predicted to have regulatory influence) that are associated with immune tolerance. In the Early Phase of MAP infection, multiple pathways were initiated in response to MAP invasion via receptor mediated endocytosis and changes in intestinal permeability. During the Intermediate Phase, perturbed pathways involved the inflammatory responses, cytokine-cytokine receptor interaction, and cell-cell signaling. During the Late Phase of infection, gene responses associated with immune tolerance were initiated at the level of T-cell signaling. Our study provides evidence that MAP infection resulted in differentially regulated genes, perturbed pathways and specifically modified mechanistic genes contributing to the colonization of Peyer's patch.en
dc.description.sponsorshipThe study was supported by funds to Sangeeta Khare from the U.S. Department of Agriculture Cooperative State Research, Education and Extension Service-National Research Initiative-Coordinated Agricultural Project-Johne's Disease Integrated Program (2004-35605-14243 sub-award Q6286224133) and Animal Health formula funds through Texas A&M University. This study was also supported by funds awarded to Leslie Garry Adams from the Texas A&M University Life Sciences Task Force. Sara D. Lawhon was supported by National Institutes of Health (U.S.) NIH-NIAID AI060933. The computational analysis work was supported in part by NIH NIAID SBIR grants 2R44AI058362-02 and R43AI084223-01 awarded to Kenneth L. Drake. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.citationKhare S, Lawhon SD, Drake KL, Nunes JES, Figueiredo JF, et al. (2012) Systems Biology Analysis of Gene Expression during In Vivo Mycobacterium avium paratuberculosis Enteric Colonization Reveals Role for Immune Tolerance. PLoS ONE 7(8): e42127.en
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0042127en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://hdl.handle.net/10919/48994en
dc.identifier.urlhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0042127en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectAmino acid metabolismen
dc.subjectCell metabolismen
dc.subjectCytokinesen
dc.subjectImmune responseen
dc.subjectMetabolic pathwaysen
dc.subjectProtein kinase signaling cascadeen
dc.subjectT cellsen
dc.subjectXenobiotic metabolismen
dc.titleSystems Biology Analysis of Gene Expression during In Vivo Mycobacterium avium paratuberculosis Enteric Colonization Reveals Role for Immune Toleranceen
dc.title.serialPLoS ONEen
dc.typeArticle - Refereeden

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