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.
Highlights
Brucellosis is a worldwide anthropozoonotic infectious disease caused by small aerobic, non-motile, Gram negative coccobacilli belonging to the genus Brucella
B. melitensis enter through the oral mucosa and colonize the lymph nodes that drain the eye, nose and mouth [11], several studies have isolated Brucella from different sections of the alimentary tract [12] and feces [13] revealing that brucellae survive under the different environmental conditions of the alimentary canal and invade in multiple sites of the gastrointestinal tract
While it is accepted that the alimentary tract is the main route of invasion for B. abortus and B. melitensis [1,10], the specific portal(s) of entry are not well defined
Summary
Brucellosis is a worldwide anthropozoonotic infectious disease caused by small aerobic, non-motile, Gram negative coccobacilli belonging to the genus Brucella. The traditional classification of Brucella species (B. melitensis, B. abortus, B. suis, B. canis, B. ovis and B. neotomae) is based on host preference [1]. Brucella spp. produce chronic infections with persistent or recurrent bacteremia, and in middle to late gestation abortion in pregnant animals. With the exception of B. ovis and B. neotomae that are exclusively pathogenic in their primary hosts (sheep and desert rat wood, respectively), and the newest Brucella species whose host specificity has yet to be fully evaluated, brucellae are able to infect other susceptible animals with similar pathogenic effect and clinical disease [5]. B. melitensis can infect cattle, among which it can be transmitted under specific epidemiological conditions [6,7,8], and it causes the most severe and acute symptoms in human beings [9]. B. melitensis enter through the oral mucosa and colonize the lymph nodes that drain the eye, nose and mouth [11], several studies have isolated Brucella from different sections of the alimentary tract [12] and feces [13] revealing that brucellae survive under the different environmental conditions of the alimentary canal and invade in multiple sites of the gastrointestinal tract
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