Elsevier

Veterinary Microbiology

Volume 90, Issues 1–4, 20 December 2002, Pages 317-328
Veterinary Microbiology

Fun stories about Brucella: the “furtive nasty bug”

https://doi.org/10.1016/S0378-1135(02)00208-0Get rights and content

Abstract

Although Brucella is responsible for one of the major worldwide zoonosis, our understanding of its pathogenesis remains in its infancy. In this paper, we summarize some of the research in progress in our laboratory that we think could contribute to a better understanding of the Brucella molecular virulence mechanisms and their regulation.

Introduction

Brucella was called “nasty” by Moreno and Moriyon in their commentary paper on the genomic sequence of Brucella melitensis published by DelVecchio and co-workers (DelVecchio et al., 2002, Moreno and Moriyon, 2002). Brucella is “furtive” as well. Unlike many other pathogenic bacteria, Brucella lacks obvious classical virulence factors such as capsules, fimbriae, flagella, exotoxins, exoenzymes including exoproteases, cytolysins, resistance forms, antigenic variation, plasmids and lysogenic phages. Further, Brucella is a facultative intracellular pathogen of both professional and non-professional phagocytic cells, hiding within the immune system from the immune system!

In the last decade, several technical improvements such as transposon mutagenesis, in vivo expression technology (IVET), differential fluorescence induction (DFI), and signature tagged mutagenesis (STM) have made it possible to analyze the molecular basis of microbial pathogenesis on a genome wide basis. In conjunction with the emerging discipline of cellular microbiology and its satellite techniques (confocal microscopy, etc.), the study of the host–pathogen relationships has progressed rapidly. The Brucella scientific community seized the opportunities offered by these powerful approaches to learn the secrets of the pathogenesis of their favorite bacterial pathogen.

The ever-increasing reports on the virulence determinants of Brucella have been reviewed recently (Boschiroli et al., 2001). Our team is very involved in the identification of virulence genes and in deciphering the virulence mechanisms of Brucella (Godfroid et al., 1998, Godfroid et al., 2000, Lestrate et al., 2000, Delrue et al., 2001). The purpose of this paper is not to make a complete survey of what has already been published by ourselves and others but, rather, to focus on three amazing and intriguing stories of Brucella that we discovered and are presently investigating further: communication by quorum sensing, flagellar apparatus without motility, and cell cycle regulation.

Section snippets

To communicate or not to communicate: the quorum sensing story

A novel communication circuit called quorum sensing (QS) that is involved in the regulation of virulence gene expression among diverse bacterial species and dependent on the number of cells was described recently (Fuqua et al., 2001). Quorum sensing describes a phenomenon in which the accumulation of a signal or actor molecule called a pheromone allows individual cells to perceive when a minimum bacteria number or quorum is reached. The signal allows for the initiation of a concerted response

To move or to secrete: the story of the flagellar gene clusters in Brucella

Eighty percent of the known bacterial species are flagellated. Assembly of a flagellum and the taxis system require around 50 genes and 1% of the energy of the cell (Macnab, 1996). Search for a favorable niche is the obvious function of flagellum based mobility but, in pathogenic bacteria, this structure could also play a role in colonization or adhesion. The homology between subunits that form the protein transport apparatus of the flagellum and the contact dependent type III secretion

Peculiarities of the cell cycle control in Brucella: the CtrA regulon story

The ctrA gene (cell cycle transcriptional regulator A) identified first in the asymmetrically dividing α-Proteobacterium C. crescentus (Quon et al., 1996) encodes an essential response regulator belonging to the OmpR family of two-component signal transduction proteins (Volz, 1993). In C. crescentus, CtrA is a global regulator that orchestrates many cell cycle events through the transcriptional control of about one fourth of the cell cycle-regulated genes (Laub et al., 2000): (1) CtrA represses

Conclusion

We are still far from understanding the regulation and the fine tuning of the molecular mechanisms of Brucella and, finally, how this bacteria causes brucellosis. Not all virulence factors are known and, for those that are known, the cellular targets they interact with or interfere with still need to be identified. One of the ways will be to identify the common mechanisms shared with plant pathogens and endosymbionts of the α-Proteobacteria because genes involved in the virulence of A.

Acknowledgements

This work was supported by the Commission of the European Communities, contract no. QLK2-CT-1999-00014. R.-M. Delrue, B. Taminiau, I. Danese, F. Bellefontaine, D. Fretin, A. Dricot, C. Deschamps and S. Leonard received a specialization grant from the Fonds pour la Formation à la Recherche dans l’Industrie et l’Agriculture.

References (54)

  • A.-F. Bellefontaine et al.

    Plasticity of transcriptional regulation network among α-Proteobacteria is supported by the identification of CtrA targets in Brucella abortus

    Mol. Microbiol.

    (2002)
  • M.L. Boschiroli et al.

    The Brucella suis virB operon is induced intracellularly in macrophages

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • G. Briones et al.

    Brucella abortus cyclic β-1,2-glucan mutants have reduced virulence in mice and are defective in intracellular replication in HeLa cells

    Infect. Immun.

    (2001)
  • D. Capela et al.

    Analysis of the chromosome sequence of the legume symbiont Sinorhizobium meliloti strain 1021

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • R. D’Ari

    Cycle-regulated genes and cell cycle regulation

    BioEssays

    (2001)
  • R.-M. Delrue et al.

    Identification of Brucella spp. genes involved in intracellular trafficking

    Cell. Microbiol.

    (2001)
  • V.G. DelVecchio et al.

    The genome sequence of the facultative intracellular pathogen Brucella melitensis

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • I.J. Domian et al.

    Feedback control of a master bacterial cell cycle regulator

    Proc. Natl. Acad. Sci. U.S.A.

    (1999)
  • L. Eskra et al.

    Brucella abortus genes identified following constitutive growth and macrophage infection

    Infect. Immun.

    (2001)
  • T.M. Finan et al.

    The complete sequence of the 1683 kb pSymB megaplasmid from the N2-fixing endosymbiont Sinorhizobium meliloti

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • C. Fuqua et al.

    Regulation of gene expression by cell-to-cell communication: acyl-homoserine lactone quorum sensing

    Annu. Rev. Genet.

    (2001)
  • F. Galibert et al.

    The composite genome of the legume symbiont Sinorhizobium meliloti

    Science

    (2001)
  • F. Godfroid et al.

    Identification of the perosamine synthetase gene of Brucella melitensis 16M and involvement of lipopolysaccharide O side chain in Brucella survival in mice and in macrophages

    Infect. Immun.

    (1998)
  • S. Halling

    On the presence and organization of open reading frames of the non-motile pathogen Brucella abortus similar to class II, III and IV flagellar genes and to LcrD virulence superfamily

    Microbial. Comp. Genomics

    (1998)
  • M.T. Holden et al.

    Quorum-sensing cross talk: isolation and chemical characterization of cyclic dipeptides from Pseudomonas aeruginosa and other Gram-negative bacteria

    Mol. Microbiol.

    (1999)
  • N. Inon de Iannino et al.

    Molecular cloning and characterization of cgs, the Brucella abortus cyclic β-1,2-glucan synthetase gene: genetic complementation of Rhizobium meliloti ndvB and Agrobacterium tumefaciens chvB mutants

    J. Bacteriol.

    (1998)
  • L.S. Kahng et al.

    The CcrM DNA methyltransferase of Agrobacterium tumefaciens is essential, and its activity is cell cycle regulated

    J. Bacteriol.

    (2001)
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