Epithelia are highly organised structures protecting underlying tissues against microbial pathogens. Epithelial morphogenesis and maintenance is mediated by cell-cell adhesion molecules organised in junctional complexes, such as the adherens junctions. The tight organisation of these complexes and their interactions with cellular factors render the epithelia impermeable to potential invaders. Nevertheless, pathogens have developed strategies to target, interact and manipulate junctional complexes, in order to disrupt or cross the epithelial barriers and cause infection. Bacteria, viruses and parasites access the junctional molecular components either directly, often taking advantage of physiological alterations in epithelial polarity, or indirectly, by delivering into cells molecular factors that destabilise junctional integrity. Importantly, microbial interactions with junctional components are instrumental not only to elucidate mechanisms of invasion, but also to unravel fundamental physiological properties of the epithelial barriers, at the cellular and tissular level.
[Show abstract][Hide abstract] ABSTRACT: Brucella melitensis causes the most severe and acute symptoms of all Brucella species in human beings and infects hosts primarily through the oral route. The epithelium covering domed villi of jejunal-ileal Peyer's patches is an important site of entry for several pathogens, including Brucella. Here, we use the calf ligated ileal loop model to study temporal in vivo Brucella-infected host molecular and morphological responses. Our results document Brucella bacteremia occurring within 30 min after intraluminal inoculation of the ileum without histopathologic traces of lesions. Based on a system biology Dynamic Bayesian Network modeling approach (DBN) of microarray data, a very early transient perturbation of the host enteric transcriptome was associated with the initial host response to Brucella contact that is rapidly averted allowing invasion and dissemination. A detailed analysis revealed active expression of Syndecan 2, Integrin alpha L and Integrin beta 2 genes, which may favor initial Brucella adhesion. Also, two intestinal barrier-related pathways (Tight Junction and Trefoil Factors Initiated Mucosal Healing) were significantly repressed in the early stage of infection, suggesting subversion of mucosal epithelial barrier function to facilitate Brucella transepithelial migration. Simultaneously, the strong activation of the innate immune response pathways would suggest that the host mounts an appropriate protective immune response; however, the expression of the two key genes that encode innate immunity anti-Brucella cytokines such as TNF-α and IL12p40 were not significantly changed throughout the study. Furthermore, the defective expression of Toll-Like Receptor Signaling pathways may partially explain the lack of proinflammatory cytokine production and consequently the absence of morphologically detectable inflammation at the site of infection. Cumulatively, our results indicate that the in vivo pathogenesis of the early infectious process of Brucella is primarily accomplished by compromising the mucosal immune barrier and subverting critical immune response mechanisms.
PLoS ONE 12/2013; 8(12):e81719. DOI:10.1371/journal.pone.0081719 · 3.23 Impact Factor
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