Hostname: page-component-848d4c4894-p2v8j Total loading time: 0.001 Render date: 2024-05-20T10:41:56.248Z Has data issue: false hasContentIssue false

Virulence factors in brucellosis: implications for aetiopathogenesis and treatment

Published online by Cambridge University Press:  19 December 2007

Emilie Fugier
Centre d'Immunologie de Marseille Luminy (CIML), Inserm U631, CNRS, Aix-Marseille University, Marseille, France.
Georgios Pappas
Institute of Continuing Medical Education of Ioannina, H. Trikoupi 10, Ioannina 45333, Greece.
Jean-Pierre Gorvel*
Centre d'Immunologie de Marseille Luminy (CIML), Inserm U631, CNRS, Aix-Marseille University, Marseille, France.
*Corresponding author: Jean-Pierre Gorvel, Centre d'Immunologie de Marseille Luminy (CIML), Inserm U631, CNRS UMR 6102, Aix-Marseille University, Case 906, 13288 Marseille Cedex 09, France. Tel:  +33 491 269 418; Fax:  +33 491 269 426; E-mail:


Brucella species are responsible for the global zoonotic disease brucellosis. These intracellular pathogens express a set of factors – including lipopolysaccharides, virulence regulator proteins and phosphatidylcholine – to ensure their full virulence. Some virulence factors are essential for invasion of the host cell, whereas others are crucial to avoid elimination by the host. They allow Brucella spp. to survive and proliferate within its replicative vacuole and enable the bacteria to escape detection by the host immune system. Several strategies have been used to develop animal vaccines against brucellosis, but no adequate vaccine yet exists to cure the disease in humans. This is probably due to the complicated pathophysiology of human Brucella spp. infection, which is different than in animal models. Here we review Brucella spp. virulence factors and how they control bacterial trafficking within the host cell.

Review Article
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)



1Bricker, B.J. et al. (2000) Molecular characterization of Brucella strains isolated from marine mammals. J Clin Microbiol 38, 1258-62CrossRefGoogle ScholarPubMed
2Nielsen, O. et al. (2001) Serologic survey of Brucella spp. antibodies in some marine mammals of North America. J Wildl Dis 37, 89-100CrossRefGoogle ScholarPubMed
3Corbel, M.J. (1997) Brucellosis: an overview. Emerg Infect Dis 3, 213-21CrossRefGoogle ScholarPubMed
4Davis, D.S. and Elzer, P.H. (2002) Brucella vaccines in wildlife. Vet Microbiol 90, 533-544CrossRefGoogle ScholarPubMed
5Boschiroli, M.L., Foulongne, V. and O'Callaghan, D. (2001) Brucellosis: a worldwide zoonosis. Curr Opin Microbiol 4, 58-64CrossRefGoogle ScholarPubMed
6Bouza, E. et al. (2005) Laboratory-acquired brucellosis: a Spanish national survey. J Hosp Infect 61, 80-83CrossRefGoogle ScholarPubMed
7Pappas, G. et al. (2006) Brucella as a biological weapon. Cell Mol Life Sci 63, 2229-2236CrossRefGoogle ScholarPubMed
8Banai, M. (2002) Control of small ruminant brucellosis by use of Brucella melitensis Rev.1 vaccine: laboratory aspects and field observations. Vet Microbiol 90, 497-519CrossRefGoogle ScholarPubMed
9Blasco, J.M. and Diaz, R. (1993) Brucella melitensis Rev-1 vaccine as a cause of human brucellosis. Lancet 342, 805CrossRefGoogle ScholarPubMed
10Moriyon, I. et al. (2004) Rough vaccines in animal brucellosis: structural and genetic basis and present status. Vet Res 35, 1-38CrossRefGoogle ScholarPubMed
11Nicoletti, P. (1990) Vaccination against Brucella. Adv Biotechnol Processes 13, 147-168Google ScholarPubMed
12Young, E.J. et al. (2000) Thrombocytopenic purpura associated with brucellosis: report of 2 cases and literature review. Clin Infect Dis 31, 904-909CrossRefGoogle ScholarPubMed
13Celli, J. et al. (2003) Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J Exp Med 198, 545-556CrossRefGoogle ScholarPubMed
14Liautard, J.P. et al. (1996) Interactions between professional phagocytes and Brucella spp. Microbiologia 12, 197-206Google ScholarPubMed
15Pizarro-Cerda, J. et al. (1998) Brucella abortus transits through the autophagic pathway and replicates in the endoplasmic reticulum of nonprofessional phagocytes. Infect Immun 66, 5711-5724CrossRefGoogle ScholarPubMed
16Pizarro-Cerda, J., Moreno, E. and Gorvel, J.P. (2000) Invasion and intracellular trafficking of Brucella abortus in nonphagocytic cells. Microbes Infect 2, 829-835CrossRefGoogle ScholarPubMed
17Delrue, R.M. et al. (2001) Identification of Brucella spp. genes involved in intracellular trafficking. Cell Microbiol 3, 487-497CrossRefGoogle ScholarPubMed
18Kohler, S. et al. (2003) What is the nature of the replicative niche of a stealthy bug named Brucella? Trends Microbiol 11, 215-219CrossRefGoogle ScholarPubMed
19Kohler, S. et al. (2002) The intramacrophagic environment of Brucella suis and bacterial response. Vet Microbiol 90, 299-309CrossRefGoogle ScholarPubMed
20Keleti, G., Feingold, D.S. and Youngner, J.S. (1974) Interferon induction in mice by lipopolysaccharide from Brucella abortus. Infect Immun 10, 282-283CrossRefGoogle ScholarPubMed
21Moreno, E., Berman, D.T. and Boettcher, L.A. (1981) Biological activities of Brucella abortus lipopolysaccharides. Infect Immun 31, 362-370CrossRefGoogle ScholarPubMed
22Goldstein, J. et al. (1992) Lipopolysaccharide (LPS) from Brucella abortus is less toxic than that from Escherichia coli, suggesting the possible use of B. abortus or LPS from B. abortus as a carrier in vaccines. Infect Immun 60, 1385-1389CrossRefGoogle ScholarPubMed
23Rasool, O. et al. (1992) Effect of Brucella abortus lipopolysaccharide on oxidative metabolism and lysozyme release by human neutrophils. Infect Immun 60, 1699-1702CrossRefGoogle ScholarPubMed
24Riley, L.K. and Robertson, D.C. (1984) Brucellacidal activity of human and bovine polymorphonuclear leukocyte granule extracts against smooth and rough strains of Brucella abortus. Infect Immun 46, 231-236CrossRefGoogle ScholarPubMed
25Lapaque, N. et al. (2006) Differential inductions of TNF-alpha and IGTP, IIGP by structurally diverse classic and non-classic lipopolysaccharides. Cell Microbiol 8, 401-413CrossRefGoogle ScholarPubMed
26Eisenschenk, F.C., Houle, J.J. and Hoffmann, E.M. (1999) Mechanism of serum resistance among Brucella abortus isolates. Vet Microbiol 68, 235-244CrossRefGoogle ScholarPubMed
27Martinez de Tejada, G. et al. (1995) The outer membranes of Brucella spp. are resistant to bactericidal cationic peptides. Infect Immun 63, 3054-3061CrossRefGoogle ScholarPubMed
28Freer, E. et al. (1996) Brucella-Salmonella lipopolysaccharide chimeras are less permeable to hydrophobic probes and more sensitive to cationic peptides and EDTA than are their native Brucella sp. counterparts. J Bacteriol 178, 5867-5876CrossRefGoogle ScholarPubMed
29Velasco, J. et al. (2000) Brucella abortus and its closest phylogenetic relative, Ochrobactrum spp., differ in outer membrane permeability and cationic peptide resistance. Infect Immun 68, 3210-3218CrossRefGoogle ScholarPubMed
30Sola-Landa, A. et al. (1998) A two-component regulatory system playing a critical role in plant pathogens and endosymbionts is present in Brucella abortus and controls cell invasion and virulence. Mol Microbiol 29, 125-138CrossRefGoogle ScholarPubMed
31Detilleux, P.G., Deyoe, B.L. and Cheville, N.F. (1990) Penetration and intracellular growth of Brucella abortus in nonphagocytic cells in vitro. Infect Immun 58, 2320-2328CrossRefGoogle ScholarPubMed
32Porte, F. et al. (2003) Role of the Brucella suis lipopolysaccharide O antigen in phagosomal genesis and in inhibition of phagosome-lysosome fusion in murine macrophages. Infect Immun 71, 1481-1490CrossRefGoogle ScholarPubMed
33Jimenez de Bagues, M.P. et al. (2004) Different responses of macrophages to smooth and rough Brucella spp.: relationship to virulence. Infect Immun 72, 2429-2433CrossRefGoogle ScholarPubMed
34Forestier, C. et al. (1999) Lysosomal accumulation and recycling of lipopolysaccharide to the cell surface of murine macrophages, an in vitro and in vivo study. J Immunol 162, 6784-6791CrossRefGoogle Scholar
35Forestier, C. et al. (1999) Interaction of Brucella abortus lipopolysaccharide with major histocompatibility complex class II molecules in B lymphocytes. Infect Immun 67, 4048-4054CrossRefGoogle ScholarPubMed
36Forestier, C. et al. (2000) Brucella abortus lipopolysaccharide in murine peritoneal macrophages acts as a down-regulator of T cell activation. J Immunol 165, 5202-5210CrossRefGoogle ScholarPubMed
37Guzman-Verri, C. et al. (2002) The two-component system BvrR/BvrS essential for Brucella abortus virulence regulates the expression of outer membrane proteins with counterparts in members of the Rhizobiaceae. Proc Natl Acad Sci U S A 99, 12375-12380CrossRefGoogle ScholarPubMed
38Lamontagne, J. et al. (2007) Extensive cell envelope modulation is associated with virulence in Brucella abortus. J Proteome Res 6, 1519-1529CrossRefGoogle ScholarPubMed
39Guzman-Verri, C. et al. (2001) GTPases of the Rho subfamily are required for Brucella abortus internalization in nonprofessional phagocytes: direct activation of Cdc42. J Biol Chem 276, 44435-44443CrossRefGoogle ScholarPubMed
40Manterola, L. et al. (2005) The lipopolysaccharide of Brucella abortus BvrS/BvrR mutants contains lipid A modifications and has higher affinity for bactericidal cationic peptides. J Bacteriol 187, 5631-5639CrossRefGoogle ScholarPubMed
41O'Callaghan, D. et al. (1999) A homologue of the Agrobacterium tumefaciens VirB and Bordetella pertussis Ptl type IV secretion systems is essential for intracellular survival of Brucella suis. Mol Microbiol 33, 1210-1220CrossRefGoogle ScholarPubMed
42Porte, F., Liautard, J.P. and Kohler, S. (1999) Early acidification of phagosomes containing Brucella suis is essential for intracellular survival in murine macrophages. Infect Immun 67, 4041-4047CrossRefGoogle ScholarPubMed
43Cascales, E. and Christie, P.J. (2003) The versatile bacterial type IV secretion systems. Nat Rev Microbiol 1, 137-149CrossRefGoogle ScholarPubMed
44Christie, P.J. (1997) Agrobacterium tumefaciens T-complex transport apparatus: a paradigm for a new family of multifunctional transporters in eubacteria. J Bacteriol 179, 3085-3094CrossRefGoogle ScholarPubMed
45Covacci, A. and Rappuoli, R. (1993) Pertussis toxin export requires accessory genes located downstream from the pertussis toxin operon. Mol Microbiol 8, 429-434CrossRefGoogle ScholarPubMed
46Bardill, J.P., Miller, J.L. and Vogel, J.P. (2005) IcmS-dependent translocation of SdeA into macrophages by the Legionella pneumophila type IV secretion system. Mol Microbiol 56, 90-103CrossRefGoogle ScholarPubMed
47Ward, D.V. et al. (2002) Peptide linkage mapping of the Agrobacterium tumefaciens vir-encoded type IV secretion system reveals protein subassemblies. Proc Natl Acad Sci U S A 99, 11493-11500CrossRefGoogle ScholarPubMed
48Comerci, D. J. et al. (2001) Essential role of the VirB machinery in the maturation of the Brucella abortus-containing vacuole. Cell Microbiol 3, 159-168CrossRefGoogle ScholarPubMed
49Kahl-McDonagh, M.M. et al. (2006) Evaluation of novel Brucella melitensis unmarked deletion mutants for safety and efficacy in the goat model of brucellosis. Vaccine 24, 5169-5177CrossRefGoogle ScholarPubMed
50Arellano-Reynoso, B. et al. (2005) Cyclic beta-1,2-glucan is a Brucella virulence factor required for intracellular survival. Nat Immunol 6, 618-625CrossRefGoogle ScholarPubMed
51de Iannino, N.I. et al. (2000) Osmotic regulation of cyclic 1,2-beta-glucan synthesis. Microbiology 146, 1735-1742CrossRefGoogle ScholarPubMed
52Briones, G. et al. (2001) Brucella abortus cyclic beta-1,2-glucan mutants have reduced virulence in mice and are defective in intracellular replication in HeLa cells. Infect Immun 69, 4528-4535CrossRefGoogle ScholarPubMed
53Bohin, J.P. (2000) Osmoregulated periplasmic glucans in Proteobacteria. FEMS Microbiol Lett 186, 11-19CrossRefGoogle ScholarPubMed
54Conde-Alvarez, R. et al. (2006) Synthesis of phosphatidylcholine, a typical eukaryotic phospholipid, is necessary for full virulence of the intracellular bacterial parasite Brucella abortus. Cell Microbiol 8, 1322-1335CrossRefGoogle ScholarPubMed
55Navarro, E. et al. (2006) Use of real-time quantitative polymerase chain reaction to monitor the evolution of Brucella melitensis DNA load during therapy and post-therapy follow-up in patients with brucellosis. Clin Infect Dis 42, 1266-1273CrossRefGoogle ScholarPubMed
56Pappas, G., Akritidis, N. and Tsianos, E. (2005) Effective treatments in the management of brucellosis. Expert Opin Pharmacother 6, 201-209CrossRefGoogle ScholarPubMed
57Solera, J. et al. (2004) A randomized, double-blind study to assess the optimal duration of doxycycline treatment for human brucellosis. Clin Infect Dis 39, 1776-1782CrossRefGoogle ScholarPubMed
58Al Dahouk, S. et al. (2005) Failure of a short-term antibiotic therapy for human brucellosis using ciprofloxacin. A study on in vitro susceptibility of Brucella strains. Chemotherapy 51, 352-356CrossRefGoogle Scholar
59Al-Mariri, A. et al. (2001) Induction of immune response in BALB/c mice with a DNA vaccine encoding bacterioferritin or P39 of Brucella spp. Infect Immun 69, 6264-6270CrossRefGoogle ScholarPubMed
60Cassataro, J. et al. (2007) A DNA vaccine coding for the chimera BLSOmp31 induced a better degree of protection against B. ovis and a similar degree of protection against B. melitensis than Rev.1 vaccination. Vaccine 25, 5958-5967CrossRefGoogle Scholar
61Cassataro, J. et al. (2005) A DNA vaccine coding for the Brucella outer membrane protein 31 confers protection against B. melitensis and B. ovis infection by eliciting a specific cytotoxic response. Infect Immun 73, 6537-6546CrossRefGoogle Scholar
62Munoz-Montesino, C. et al. (2004) Intraspleen delivery of a DNA vaccine coding for superoxide dismutase (SOD) of Brucella abortus induces SOD-specific CD4+ and CD8+ T cells. Infect Immun 72, 2081-2087CrossRefGoogle ScholarPubMed
63Yu, D.H., Hu, X.D. and Cai, H. (2007) A combined DNA vaccine encoding BCSP31, SOD, and L7/L12 confers high protection against Brucella abortus 2308 by inducing specific CTL responses. DNA Cell Biol 26, 435-443CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Gorvel, J.P., ed. (2003) Intracellular Pathogens in Membrane Interactions and Vacuole Biogenesis, Landes Bioscience/Eurekah.comCrossRefGoogle Scholar