昭和20年代, 教室の日常と研究余話(第922回千葉医学会例会・第13回千葉精神科集談会)

<p>Unique MAA Arcs and Mechanistic Genes in Tight Junction Pathway.</p

Systems Analysis of Early Host Gene Expression Provides Clues for Transient <i>Mycobacterium avium</i> ssp <i>avium</i> vs. Persistent <i>Mycobacterium avium</i> ssp <i>paratuberculosis</i> Intestinal Infections

<div><p>It has long been a quest in ruminants to understand how two very similar mycobacterial species, <i>Mycobacterium avium</i> ssp. p<i>aratuberculosis</i> (MAP) and <i>Mycobacterium avium</i> ssp. <i>avium</i> (MAA) lead to either a chronic persistent infection or a rapid-transient infection, respectively. Here, we hypothesized that when the host immune response is activated by MAP or MAA, the outcome of the infection depends on the early activation of signaling molecules and host temporal gene expression. To test our hypothesis, ligated jejuno-ileal loops including Peyer’s patches in neonatal calves were inoculated with PBS, MAP, or MAA. A temporal analysis of the host transcriptome profile was conducted at several times post-infection (0.5, 1, 2, 4, 8 and 12 hours). When comparing the transcriptional responses of calves infected with the MAA versus MAP, discordant patterns of mucosal expression were clearly evident, and the numbers of unique transcripts altered were moderately less for MAA-infected tissue than were mucosal tissues infected with the MAP. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis. Bayesian network modeling identified mechanistic genes, gene-to-gene relationships, pathways and Gene Ontologies (GO) biological processes that are involved in specific cell activation during infection. MAP and MAA had significant different pathway perturbation at 0.5 and 12 hours post inoculation. Inverse processes were observed between MAP and MAA response for epithelial cell proliferation, negative regulation of chemotaxis, cell-cell adhesion mediated by integrin and regulation of cytokine-mediated signaling. MAP inoculated tissue had significantly lower expression of phagocytosis receptors such as mannose receptor and complement receptors. This study reveals that perturbation of genes and cellular pathways during MAP infection resulted in host evasion by mucosal membrane barrier weakening to access entry in the ileum, inhibition of Ca signaling associated with decreased phagosome-lysosome fusion as well as phagocytosis inhibition, bias toward Th2 cell immune response accompanied by cell recruitment, cell proliferation and cell differentiation; leading to persistent infection. Contrarily, MAA infection was related to cellular responses associated with activation of molecular pathways that release chemicals and cytokines involved with containment of infection and a strong bias toward Th1 immune response, resulting in a transient infection.</p></div

Early and Late Stage Pathway and Gene Ontologies Having Reversed and unique Perturbation States during MAP and MAA Interaction.

<p>Early and Late Stage Pathway and Gene Ontologies Having Reversed and unique Perturbation States during MAP and MAA Interaction.</p

Venn diagram comparison of the number of unique and common mechanistic genes found for the MAP and MAA conditions.

<p>Only the mechanistic genes from the pathways and GO terms listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161946#pone.0161946.t003" target="_blank">Table 3</a> were used in creating this diagram.</p

Invasion of Jejunal and Jejuno-ileal Mucosa by MAP and MAA.

<p>Invasion of Jejunal and Jejuno-ileal Mucosa by MAP and MAA.</p

Heatmap of pathway scores of a side-by-side comparison (by time point) between MAP vs PBS versus MAA vs PBS.

<p>The heatmap compares MAP significantly perturbed pathways to the MAA condition. The selection of pathways was based on those that were found significant (DBGGA zscore ≥ 2.24) for the MAP condition at 30 minutes post infection. Red indicates activation and green indicates repression. The gradient in color indicates magnitude of perturbation (i.e., higher |zscore|).</p

Illustrative Interrogation of the Model for Mechanistic <i>AKT3</i> Gene Downstream Regulatory Effects on Multiple Pathways.

<p>Illustrative Interrogation of the Model for Mechanistic <i>AKT3</i> Gene Downstream Regulatory Effects on Multiple Pathways.</p

Key Down-Regulated Mechanistic Genes of the CCR3 Signaling in Eosinophil Pathway.

<p>Key Down-Regulated Mechanistic Genes of the CCR3 Signaling in Eosinophil Pathway.</p

System Bayesian Network Model of Host Immune Tolerance.

<p>Fourteen pathways were used to construct the network developed from temporal <i>in vivo</i> host transcriptome data of MAP infected bovine Peyer's patch. The full network model is shown on the bottom figure. A magnified section of the model is shown in the top figure. Mechanistic genes are shown with orange rings. A few important mechanistic genes and arcs (gene-to-gene relationships) are indicated on the magnified view. The thickness of the arcs and their color indicates the strength of positive or negative correlation between the interconnected genes. Some of the pathway arcs are labled: +p = phosphorylation; −p = dephosphorylation; +u = ubiquitination; +m = methylation; e = expression;c = compound; and b = binding and unlabeled connecting arc implies activation.</p

Junction (Gap, Tight, Adherens) Pathways Mechanistic Genes.

<p>Junction (Gap, Tight, Adherens) Pathways Mechanistic Genes.</p