Toxins and Bacterial Pathogenesis - URA 2172 CNRS  


  HEADDr MOCK Michèle / mmock@pasteur.fr
  MEMBERSBERTIN Marine / CHATEAU Alice / CORRE Jean-Philippe / COUTURE-TOSI Evelyne / DAVISON Sophie / DOMAINGUE Priscilla / Dr DUMETZ Fabien / FERRAND Mireille / Dr FOUET Agnès / Dr GLOMSKI Ian / Dr Méd. GOOSSENS Pierre
HAUSTANT Georges / Dr KIMURA Keitarou / Dr MARY-POSSOT Odile / Dr MELONI Mauro / Dr MOYA-NILGES Marie / NICHOLS Scott / Dr RANCK Jean-Luc / SCHWARTZ Marie / SMEETS Fabien M.H. / Dr SYLVESTRE Patricia


  Annual Report

Introduction

Bacillus anthracis, the aetiological agent of anthrax, is a Gram-positive, spore-forming, extracellular bacterium. The spore is both the form of persistance in the environment and the infectant form. Two toxins, and a poly-glutamic acid, antiphagocytic, capsule are the main virulence factors

Spore surface

The exosporium is the most external structure of the spore. It consists of a paracrystalline basal layer and of BclA, a collagen-like glycoprotein. Other spore components required for the assembly of the paracrystalline layer have been identified.

Metabolic pathways and biodiversity

Among the main groups defined world-wide for B. anthracis strains, those of the sub-group B2, mostly found in France, exhibit specific sugar utilisation. A1 strains use starch but not gluconate, and conversely for B2 strains. A comparative genomic analysis has revealed mutations affecting enzyme activities potentially involved in sugar utilisation.

Vegetative form surface

Four proteins are necessary for capsule synthesis. A fifth protein catalyzes the capsule covalent anchoring to the peptidoglycan.

“Sortases” catalyze the covalent anchoring of proteins harboring an “LPXTG” motif. B. anthracis possesses three sortases and 14 “LPXTG” proteins. We have constructed mutants of each of the sortases. We have characterized an “LPXTG” protein that is anchored by sortase A. We are defining B. anthracis sortase repertoires.

Regulation of virulence factors synthesis

Toxin components are maximally synthesized at the end of the exponential phase. Transition state regulators, including CodY, repress gene expression during exponential phase. CodY implication in toxin, capsule and AtxA, a B. anthracis master regulator, gene expression is under study. B. anthracis stringent response has been characterized. There is a single rel gene in B. anthracis.

Animal models

In vivo real time analysis of bioluminescent B. anthracis dissemination during cutaneous, inhalational and gastrointestinal infection in mice (Figure) has shown the respective role of capsule and toxins. This led to identification of previously undescribed portals of entry and target organs. Local germination occurs prior dissemination to lymph nodes.

Innate and adaptive immunity

We have shown that group IIA phospholipase A2, secreted by macrophages controls B. anthracis infection. Toxins inhibit production of this enzyme. The cell transduction pathways involved in this inhibition are analysed.

A non-living anthrax vaccine composed of protective antigen and inactivated spores has been devised for human use. We have shown that the protective immunity afforded by spore immunisation is dependent on cellular immunity involving CD4 T lymphocytes and gamma interferon.

Keywords: Anthrax, Bacillus anthracis, Spore surface, capsule, toxins, sortases, in vivo bioluminescence, regulation, immunity

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  Publications

Van Schaik, W., J. Prigent, and A. Fouet. 2007. The stringent response of Bacillus anthracis contributes to sporulation but not to virulence. Microbiology 153: 4234-4239. (PMID: 18048936)

Glomski I. J., A. Piris-Giménez, M. Huerre, M. Mock, and P. L. Goossens. 2007. Primary involvement of pharynx and peyer's patch in inhalational and intestinal anthrax. PLoS Pathog. 3 : e76. (PMID: 17542645)

Glomski, I. J., J.-P. Corre, M. Mock, and P. L. Goossens. 2007. Cutting edge : IFN-γ-producing CD4 T lymphocytes mediate spore-induced immunity to capsulated Bacillus anthracis. J. Immunol. 178 :2646-2650. (PMID: 17312104)

Piris-Giménez, A., M. Paya, G. Lambeau, M. Chignard, M. Mock, L. Touqui, and P. L. Goossens. 2005. In vivo protective role of human group IIA phospholipase A2 against experimental anthrax. J. Immunol. 175: 6786-6791. (PMID: 16272335)

Candela, T., and A. Fouet. 2005. Bacillus anthracis CapD, belonging to the γ-glutamyltranspeptidase family, is required for the covalent anchoring of capsule to peptidoglycan. Mol. Microbiol. 57:717-726. (PMID: 16045616)





Activity Reports 2007 - Institut Pasteur
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