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  Director : MOCK Michèle (mmock@pasteur.fr)


  abstract

 

The virulence mechanisms of B. anthracis, the aetiological agent of anthrax, an extracellular, toxinogenic, bacterium, are investigated. Spores of B. anthracis germinate within the phagolysosome of macrophages and toxin expression begins at this step. The structural organisation, the cellular mode of action of toxins and their role in pathogenesis are analysed. The B. anthracis cell surface, the S-layer and capsule, and its role in the interaction of this pathogen with the host is under investigation. It was also shown that B. anthracis can be used to express foreign proteins and is therefore promising for the development of live veterinary vaccines. Genetic studies have shown that B. anthracis and B. cereus are one species.



  report

cale

Interaction of Bacillus anthracis with the host(Patricia Sylvestre - Chantal Guidi-Rontani - Michèle Mock)
The spore is both the form of persistance in the environment of B. anthracis and the infectant form starting infection after germination in the host. The exosporium is the most external structure of the spore. Its role in the early interaction with the host and its contribution to immunoprotection are analyzed. Germination of the spore can take place in the phagolysosome of macrophages , a phenomenon associated with an early synthesis of toxins. Moreover, a germination operon located on the virulent plasmid pXO1 is involved in the in vivo germination of B. anthracis.

Toxins of Bacillus anthracis — Vaccinal strategies(Fabien Brossier - Chantal Guidi-Rontani - Michèle Mock)
Bacillus anthracis secretes two toxins composed of three proteins : lethal toxin (PA + LF) and edema toxin (PA + EF). PA is the common component able to bind and deliver EF and LF into target eukaryotic cells. EF is a calmodulin-dependent adenylate cyclase and LF is a metalloprotease which acts specifically in the MAPKKinases family. LF and EF are translocated to the cytosol of sensitive cells from early endosome vesicles with different strategies. Analysis of cristal structure of PA revealed four functional domains. We have shown that domain 4 is required for the binding of PA to the cells and a 19-aminoacid loop located in this domain contributes to this property.
B. anthracis strains producing PA protein mutated in the different functional domains have been constructed.In vivo study of their properties indicates a correlation between the steps of cellular mode of action of toxins and the pathogenesis. Moreover, a strain isogenic to the vaccinal veterinary Sterne strain, producing LF and EF genetically detoxified, confers protection against anthrax lethal challenge. Recently, an acellular vaccine composition has been developped which may allow the improvement of human vaccination.

Expression of heterologous antigens by Bacillus anthracis(Fabien Brossier - Stéphane Mesnage - Michèle Mock)
It has been shown that B. anthracis recombinant strains can induced a humoral or cellular protective response depending of the heterologous antigen used. More recently, strains producing the C-fragment of tetanus toxin fused either to the N-terminal part of LF allowing a PA-mediated presentation or to the SLH domain of EA1 allowing a bacterial cell-surface anchoring have been constructed . These two different expression systems induced protection against lethal doses of tetanus toxin.

The surface(Tâm Mignot - Agnès Fouet)
The bacilli isolated from animals dying of anthrax are encapsulated. The capsule covers a structural array termed S-layer. Yet, capsule and S-layer can be independently synthesized. The S-layer is composed of two abundant proteins, Sap and EA1. These are successively synthesized, giving rise to the replacement of an S-layer by another. Sap and EA1 each have, in their N-terminal region, a sequence that is repeated three times. This domain is sufficient to anchor Sap and EA1 and heterologous proteins to a modified peptidoglycan associated polysaccharide. This non-covalent anchoring mechanism is found in many bacterial species. Inside the cereus group, the presence of an S-layer is limited to pathogenic strains.

Molecular epidemiology of anthrax in France and phylogenetic characterization of soil strains(Agnès Fouet - Michèle Mock)
Anthrax is a zoonose which attacks all mammals and mainly herbivores. Although this disease has regressed, it still exists in France where it sporadically appears each year in various regions. Little is known epidemiologically, and nothing at the molecular level, on the outcome of the B. anthracis spores in the soil. Analysis of animal and environmental samplings from recent outbreaks has shown that soil Bacillus sp. share biochemical characteristics with B. anthracis and B. thuringiensis (an entomopathogen). A thorough biomolecular study implying these bacteria and many B. cereus strains has shown that, based on genetic evidence, B. anthracis, B. cereus and B. thuringiensis are in fact one species. Also, French B. anthracis strains are extremely diverse, belonging to the two groups defined world-wide.



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
 

FERRAND Mireille, IP

FOUET AGNÈS, CNRS

GOOSSENS Pierre, IP

GUIDI-RONTANI Chantal, CNRS

POPOFF Michel-Robert, IP

BROSSIER Fabien, postdoctoral researcher

CANDELA Thomas, graduate student

JACQUET Claire, graduate student

MARVAUX Jean-Christophe, postdoctoral researcher

MIGNOT Tâm, graduate student

RAFFESTIN Stéphanie, graduate student

SYLVESTRE Patricia, graduate student

CARLIER Jean-Philippe, engineer IP

DUFLOT Edith, engineer CNRS

GIBERT Maryse, technician IP

HENRY Christine technician IP

LANDIER Ann,ie, technician IP

LEVY Martine, technician IP

LORIN Valérie technician IP


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