The Effector Protein BPE005 from Brucella abortus Induces Collagen Deposition and Matrix Metalloproteinase 9 Downmodulation via Transforming Growth Factor β1 in Hepatic Stellate Cells

• Published in: Infection and immunity 2016-02, Vol.84 (2), p.598-606
• Main Authors: Arriola Benitez, Paula Constanza, Rey Serantes, Diego, Herrmann, Claudia Karina, Pesce Viglietti, Ayelén Ivana, Vanzulli, Silvia, Giambartolomei, Guillermo Hernán, Comerci, Diego José, Delpino, María Victoria
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Infections; Bacterial Proteins - chemistry; Bacterial Proteins - isolation & purification; Bacterial Proteins - metabolism; Brucella abortus - chemistry; Brucella abortus - genetics; Brucella abortus - metabolism; Brucella abortus - pathogenicity; Brucellosis - microbiology; Brucellosis - pathology; Cell Line; Collagen - metabolism; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Down-Regulation; Female; Fibrosis; Gene Expression Regulation, Enzymologic; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - microbiology; Hepatic Stellate Cells - pathology; Liver - pathology; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice, Inbred BALB C; Phenotype; Signal Transduction; Transforming Growth Factor beta - metabolism; Type IV Secretion Systems; Virulence Factors
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.01227-15

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.