Systems biology analysis of gene expression during in vivo Mycobacterium avium paratuberculosis enteric colonization reveals role for immune tolerance.
Survival 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.
Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
Sangeeta
S
Khare
Sara D
SD
Lawhon
Kenneth L
KL
Drake
Jairo E S
JE
Nunes
Josely F
JF
Figueiredo
Carlos A
CA
Rossetti
Tamara
T
Gull
Robin E
RE
Everts
Harris A
HA
Lewin
Cristi L
CL
Galindo
Harold R
HR
Garner
Leslie Garry
LG
Adams
D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D001499:Bayes Theorem; D002417:Cattle; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010581:Peyer's Patches / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D049490:Systems Biology; D013997:Time Factors