Toxins and Bacterial Pathogenesis - URA 2172 CNRS  


  HEADDr MOCK Michèle / mmock@pasteur.fr
  MEMBERSANTUNES Ana/BENARD Maria/BERTIN Marine/CAMIADE Emilie/CHATEAU Alice/CORRE Jean-Philippe/COUTURE-TOSI Evelyne/Dr DUMETZ Fabien/Dr DUPUY Bruno/FEEHLEY Josephine Taylor/FERRAND Mireille/Dr FOUET Agnès/Dr Méd. GOOSSENS Pierre/ Dr GOVIND Revathi/HAUSTANT Georges/LÖLL Raphaël/Dr MARY-POSSOT Odile/MONOT Marc/Dr MOYA-NILGES Marie/NICHOLS Scott/Dr RANCK Jean-Luc/ SCHWARTZ Marie/Dr SYLVESTRE Patricia


  Annual Report

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

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

“Sortases” catalyze the covalent anchoring of proteins harboring an “LPXTG” motif. B. anthracis possesses three sortases and 13 “LPXTG” proteins. The latter are promiscuous substrates. The LPXTG proteins are not necessarily anchored by the predicted sortase. Some LPXTG proteins may be anchored by more than one sortase. A Gram-negative bacterium, that harbors two contiguous genes similar to two of the B. anthracis capsule biosynthetic operon genes, synthesizes poly-glutamate.

Regulation of virulence and persistence factors synthesis

Toxin components are maximally synthesized at the end of the exponential phase. CodY, a transition state regulator that represses virulence in many pathogens, activates that of B. anthracis. It controls AtxA, the master regulator, accumulation and activates the expression of the toxin genes and of most iron uptake systems. atxA previously described promoter region is insufficient for atxA full expression.

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.

Regulation of pathogenesis in Clostridium difficile

Clostridium difficile is an emerging pathogen and a leading source of often-lethal nosocomial infections. Studies are conducted on the regulation of toxin production. A new family of alternative sigma factor (ClassV) has been identified as well as regulatory pathways and their interplay with environmental sensors are being unravelled.

Keywords: Anthrax, Bacillus anthracis, Clostridium difficile, spore surface, capsule, toxins, sortases, poly-glutamate, 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)

Raymond B., D. Leduc, L. Ravaux, R. Le Goffic, T. Candela, M. Raymondjean, P.L. Goossens*, and L. Touqui*. 2007. Edema toxins impairs anthracidal phospholipase A2 expression by alveolar macrophages. PLoS Pathog. : e187. (PMID: 18069891) *(share senior co-authorship).

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 2009 - Institut Pasteur
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