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The hepatic immune system can induce rapid and controlled responses to pathogenic microorganisms and tumor cells. Accordingly, most of the microorganisms that reach the liver through the blood are eliminated. However, some of them, including Brucella spp., take advantage of the immunotolerant capacity of the liver to persist in the host. Brucella has a predilection for surviving in the reticuloendothelial system, with the liver being the largest organ of this system in the human body. Therefore, its involvement in brucellosis is practically invariable. In patients with active brucellosis, the liver is commonly affected, and the most frequent clinical manifestation is hepatosplenomegaly. The molecular mechanisms implicated in liver damage have been recently elucidated. It has been demonstrated how Brucella interacts with hepatocytes inducing its death by apoptosis. The inflammatory microenvironment and the direct effect of Brucella on hepatic stellate cells (HSC) induce their activation and turn these cells from its quiescent form to their fibrogenic phenotype. This HSC activation induced by Brucella infection relies on the presence of a functional type IV secretion system and the effector protein BPE005 through a mechanism involved in the activation of the autophagic pathway. Finally, the molecular mechanisms of liver brucellosis observed so far are shedding light on how the interaction of Brucella with liver cells may play an important role in the discovery of new targets to control the infection. In this review, we report the current understanding of the interaction between liver structural cells and immune system cells during Brucella infection., (Copyright © 2019 Giambartolomei and Delpino.)

Osteoarticular brucellosis is the most common localization of human active disease. Osteoblasts are specialized mesenchymal-derived cells involved in bone formation and are considered as professional mineralizing cells. Autophagy has been involved in osteoblast metabolism. The present study demonstrates that Brucella abortus infection induces the activation of the autophagic pathway in osteoblast cells. Autophagy was revealed by upregulation of LC3II/LC3I ratio and Beclin-1 expression as well as inhibition of p62 expression in infected cells. Induction of autophagy was also corroborated by using the pharmacological inhibitors wortmannin, a PI 3-kinase inhibitor, and leupeptin plus E64 (inhibitors of lysosomal proteases). Autophagy induction create a microenvironment that modifies osteoblast metabolism by the inhibition of the deposition of organic and mineral matrix, the induction of matrix metalloproteinase (MMP)-2, osteopontin, and RANKL secretion leading to bone loss. Accordingly, autophagy is also involved in the down-modulation of the master transcription factor in bone formation osterix during B. abortus infection. Taking together our results indicate that B. abortus induces the activation of autophagy pathway in osteoblast cells and this activation is involved in the modulation of osteoblast function and bone formation.

Neurobrucellosis is an inflammatory disease caused by the invasion of Brucella spp. to the central nervous system (CNS). The pathogenesis of the disease is not well characterized; however, for Brucella to gain access to the brain parenchyma, traversing of the blood-brain barrier (BBB) must take place. To understand the CNS determinants of the pathogenesis of B. abortus , we have used the in vitro BBB model of human brain microvascular endothelial cells (HBMEC) to study the interactions between B. abortus and brain endothelial cells. In this study, we showed that B. abortus is able to adhere and invade HBMEC which was dependent on microtubules, microfilaments, endosome acidification and de novo protein synthesis. After infection, B. abortus rapidly escapes the endosomal compartment of HBMEC and forms a replicative Brucella -containing vacuole that involves interactions with the endoplasmic reticulum. Despite the ability of B. abortus to invade and replicate in HBMEC, the bacterium was unable by itself to traverse HBMEC, but could traverse polarized HBMEC monolayers within infected monocytes. Importantly, infected monocytes that traversed the HBMEC monolayer were a bacterial source for de novo infection of glial cells. This is the first demonstration of the mechanism whereby B. abortus is able to traverse the BBB and infect cells of the CNS. These results may have important implications in our understanding of the pathogenesis of neurobrucellosis.