Dr. Rodolfo Ugalde
Institute of Biotechnology Research - UNSAM

Mechanisms of virulence of Brucella abortus

Brucella spp. are Gram-negative facultative intracellular pathogens that belong to the alpha-2 subgroup of Proteobacteria. Several genera of this group, such as Agrobacterium, Rickettsia and Rhizobium, establish close relationships with eukaryotic organisms as pathogens or as endosymbionts. Brucella spp. infect many domestic mammals causing brucellosis, a chronic infectious disease that produces abortion in pregnant females and sterility in males. Three species of the genus, Brucella abortus, Brucella melitensis and Brucella suis (whose preferred hosts are cattle, goats and pigs, respectively), are also able to produce zoonotic infections in humans. The clinical manifestations of human brucellosis are undulant fever, endocarditis, osteoarticular complications and neurological disorders, producing serious consequences in chronic cases.
Following are some examples of the mechanisms of virulence we are presently characterizing:

1. An essential trait of Brucella virulence resides in its ability to survive and replicate within infected cells. During this process, the bacterium is internalized in a vacuole and redirects its intracellular traffic in such a way that it avoids degradation by the endocytic pathway. Subsequent interaction events with endoplasmic reticulum (ER) membranes allow the maturation of the Brucella-containing vacuole (bcv) into an intracellular replication compartment where the bacterium multiplies.

2. Brucella produces cyclic ß-1,2-glucan. This compound is a cyclic homopolysaccharide consisting of about 17 to 22 ß-1,2-linked glucose units. Recently, isolation of the B. abortus cgs gene, which codes for the cyclic ß-1,2-glucan synthase, and characterization of the synthesis of cyclic ß-1,2-glucan in this species have been reported. B. abortus cgs mutants showed reduced virulence in mice and defective intracellular multiplication, indicating that cyclic glucan is required for an effective host interaction. Furthermore, cyclic glucans must be transported into the periplasmic space for activity to occur. Isolation of the B. abortus cyclic glucan transporter gene (cgt) was described recently. Cyclic glucan transporter mutations in B. abortus have also affected its interaction with the host. Thus, the presence of cyclic glucan in the periplasmic space in B. abortus is required for complete expression of virulence. Because of this, Cgs may be a good target for development of alternative chemotherapy against this pathogen.

Recent publications:
Arellano-Reynoso B, Lapaque N, Salcedo S, Briones G, Ciocchini AE, Ugalde R, Moreno E, Moriyon I, Gorvel JP. Cyclic beta-1,2-glucan is a Brucella virulence factor required for intracellular survival. Nat Immunol. 2005 6:618-25.
Sieira R, Comerci DJ, Pietrasanta LI, Ugalde RA. Integration host factor is involved in transcriptional regulation of the Brucella abortus virB operon. Mol Microbiol. 2004 Nov;54(3):808-22.
Ciocchini AE, Roset MS, Inon de Iannino N, Ugalde RA. Membrane topology analysis of cyclic glucan synthase, a virulence determinant of Brucella abortus. J Bacteriol. 2004 Nov;186(21):7205-13.
Marchesini MI, Ugalde JE, Czibener C, Comerci DJ, Ugalde RA. N-terminal-capturing screening system for the isolation of Brucella abortus genes encoding surface exposed and secreted proteins. Microb Pathog. 2004 Aug;37(2):95-105. Roset MS, Ciocchini AE, Ugalde RA, Inon de Iannino N. Molecular cloning and characterization of cgt, the Brucella abortus cyclic beta-1,2-glucan transporter gene, and its role in virulence.Infect Immun. 2004 Apr;72(4):2263-71.