The liver is frequently affected in patients with active brucellosis. In the present study, we identified a virulence factor involved in the modulation of hepatic stellate cell function and consequent fibrosis during Brucella abortus infection. This study assessed the role of BPE005 protein from B. abortus in the fibrotic phenotype induced on hepatic stellate cells during B. abortus infection in vitro and in vivo. We demonstrated that the fibrotic phenotype induced by B. abortus on hepatic stellate (LX-2) cells was dependent on BPE005, a protein associated with the type IV secretion system (T4SS) VirB from B. abortus. Our results indicated that B. abortus inhibits matrix metalloproteinase 9 (MMP-9) secretion through the activity of the BPE005-secreted protein and induces concomitant collagen deposition by LX-2 cells. BPE005 is a small protein containing a cyclic nucleotide monophosphate binding domain (cNMP) that modulates the LX-2 cell phenotype through a mechanism that is dependent on the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway. Altogether, these results indicate that B. abortus tilts LX-2 cells to a profibrogenic phenotype employing a functional T4SS and the secreted BPE005 protein through a mechanism that involves the cAMP and PKA signaling pathway. Brucellosis is a worldwide zoonosis characterized by hepatomegaly, splenomegaly, and peripheral lymphadenopathy. It is a chronic and debilitating infection caused by Gram-negative facultative intracellular bacteria that infect domestic and wild animals and that can be transmitted to humans (1, 2). The frequency of liver involvement in active brucellosis ranges from 5% to 52% or more (1). However, although numerous studies have focused on brucellar liver histopathology (1), the pathogenic mechanisms of liver disease caused by Brucella have not been completely investigated at the molecular and cellular levels.Liver fibrosis is a wound-healing response to chronic hepatic injury, which may be caused by alcohol abuse, hepatitis virus infection, or nonalcoholic steatohepatitis, and it is characterized by an excessive accumulation of extracellular matrix proteins in the liver (3, 4). An early event in the development of liver fibrosis is the activation of hepatic stellate cells (HSCs), the major cell type responsible for increased synthesis of extracellular matrix proteins (5). An elevated level of transforming growth factor 1 (TGF-1) is also observed in the damaged liver, and it has a close correlation with fibrogenic changes in HSCs and liver tissue (6-8). In addition, decreased matrix metalloproteinase 9 (MMP-9) expression was observed in alcoholic liver fibrosis (9). This fibrogenic phenotype involves alterations in the balance of MMPs and their natural inhibitors-tissue inhibitors of metalloproteinases (TIMPs). In particular, MMP-2 and MMP-9 (gelatinase A and B, respectively) are important in regulating fibrogenesis and scar degradation. They can degrade a variety of collagens, including basement membrane (type IV collagen), denatured fibrillar...
Brucella spp. are Gram-negative facultative intracellular bacteria that cause a debilitating and chronic zoonotic disease (1). Osteoarticular complications are important due to their high prevalence and also to the associated functional sequelae (2-4). Bone loss has been consistently reported in the three most frequent forms of osteoarticular brucellosis (sacroiliitis, spondylitis, and peripheral arthritis) (5-8).Although the ability of Brucella to cause bone loss is well documented, the molecular mechanisms implicated have not been completely deciphered yet. We have recently described a putative immune mechanism for inflammatory bone loss that may occur in response to infection by B. abortus. Our results revealed an important contribution of the macrophages, osteoblasts, and T lymphocytes in response to B. abortus infection and the resulting induction of osteoclast differentiation (9-11).For many years the bone-bound osteocyte has been considered a relatively inactive cell with a broadly unknown role in the bone. But osteocytes are not only the most abundant bone cells and comprise up to 95% of the bone cells in the adult skeleton but also the central regulators of the differentiation and activity of both osteoblasts and osteoclasts during bone remodeling (12). Primary osteocytes and the osteocyte cell line MLO-Y4 secrete macrophage colony-stimulating factor (M-CSF) and RANKL, both necessary for osteoclast formation (13), and recent studies showed that osteocytes are the major regulators of osteoclast formation and activation (14). In addition to the role of osteocytes in regulating bone remodeling, emerging evidence suggests an important role for the gap junction in osteoclast-osteocyte communication (15). Connexin 43 (Cx43) is the most prominent gap junction protein expressed in osteocytes (15), and deficient mice have increased bone resorption and osteoclast numbers (16,17). In vitro studies revealed that Cx43-deficient MLO-Y4 cells display an increase in the RANKL/osteoprotegerin (OPG) ratio compared to control MLO-Y4 cell levels, indicating that loss of Cx43 in osteocytes promotes osteoclastogenesis (17,18). On the other hand, it has been reported that mice lacking Cx43 in osteoblasts/osteocytes or only in osteocytes exhibit increased osteocyte apoptosis (18). Moreover, integrins can link the cellular cytoskeletal network to the extracellular matrix (19). Integrins are essential determinants of cell survival, and, in many cases, prevention or alteration of integrin adhesion triggers a form of apoptosis known as anoikis (20). In
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