Abstract
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.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / chemistry*
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Bacterial Proteins / isolation & purification
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Bacterial Proteins / metabolism
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Brucella abortus / chemistry
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Brucella abortus / genetics
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Brucella abortus / metabolism*
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Brucella abortus / pathogenicity
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Brucellosis / microbiology
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Brucellosis / pathology
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Cell Line
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Collagen / metabolism*
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Down-Regulation
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Female
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Fibrosis
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Gene Expression Regulation, Enzymologic
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Hepatic Stellate Cells / metabolism*
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Hepatic Stellate Cells / microbiology*
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Hepatic Stellate Cells / pathology
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Liver / pathology*
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Matrix Metalloproteinase 9 / genetics*
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Matrix Metalloproteinase 9 / metabolism
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Mice, Inbred BALB C
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Phenotype
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Signal Transduction
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Transforming Growth Factor beta / metabolism*
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Type IV Secretion Systems
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Virulence Factors
Substances
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Bacterial Proteins
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Transforming Growth Factor beta
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Type IV Secretion Systems
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Virulence Factors
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Collagen
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Matrix Metalloproteinase 9
Grants and funding
This work was supported by grants PICT2010-0023, PICT 2011-1501, PICT 2011-1200, PICT 2012-2252, and PICT 2011 01485 from Agencia Nacional of Promoción Científica y Tecnológica (ANPCYT, Argentina) and by grants UBACYT 20020090200012 and 20020120100128 from Universidad de Buenos Aires. P.C.A.B. and C.K.H. are recipients of a fellowship from CONICET. A.I.P.V. is a recipient of a fellowship from ANPCyT. G.H.G., D.J.C., S.V., and M.V.D. are members of the Research Career of CONICET. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.