Toxins and Bacterial Pathogenesis - URA 2172 CNRS  


  HEADDr MOCK Michèle / mmock@pasteur.fr
  MEMBERSANTUNES Ana/AUCHER Willy/Dr BARBUT Frédéric/BENARD Maria/BERTIN Marine/Dr BREZILLON Christophe/CHATEAU Alice/CORRE Jean-Philippe/COUTURE-TOSI Evelyne/Dr DUPUY Bruno/FERRAND Mireille/Dr FOUET Agnès/Dr Méd. GOOSSENS Pierre/HAUSTANT Georges/Dr LEVI-MEYRUEIS Corinne/Dr MARY-POSSOT Odile/MONOT Marc/Dr MOYA-NILGES Marie/Dr RANCK Jean-Luc /SIX Anne/STEFANI Caroline/TEYSSIERES Emilie/TOME Ana Rita Ramalho


  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 persistence in the environment and the infecting 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 forB. 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. anthracispossesses 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.

Regulation of virulence and persistence factors synthesis

CodY, a transition state regulator that represses virulence in many pathogens, activates that of B. anthracis. It controls AtxA, the pXO1-encoded master virulence regulator, accumulation at a post-translational level. atxAmRNA comprises 2 long UTRs, in 5’ and 3’ of the gene. That in 3’ contains a rho-independent terminator that stabilizes the mRNA. No pXO1-encoded element but atxA, as it is now described, is required for bicarbonate induction of a toxin gene transcription.

Animal models

In vivo real time analysis of bioluminescent B. anthracisdissemination during cutaneous, inhalational and gastrointestinal infection in mice has shown the respective role of capsule and toxins. This led to identification of previously undescribed portals of entry and target organs. We have shown a previously undescribed role for the capsule; it is an adhesin, mediating close interaction of the bacteria with vascular endothelium in vivo. This modifies the current view of B. anthracispathophysiology.

Subversion of the innate immune defenses

We have characterised how B. anthracistoxins inhibits the production of effectors of the innate immune system, such as chemokines, cytokines and the bactericidal enzyme group IIA phospholipase A2 in key target cells (alveolar macrophages, bronchial epithelial cells, dendritic cells). Detailed analysis of the disruption of the cell signal transduction pathways have shown that the end-effects involve epigenetic mechanisms leading to impaired recruitment of transcription factors on their promoter.

Regulation of pathogenesis in Clostridium difficile

Clostridium difficile is an emerging pathogen and a leading source of often-lethal nosocomial infections. The main purpose of this research is to identify and characterize all the factors that intervene in C. difficilepathogenesis including, in addition to factors involved in transport and regulation of toxins, those for which it would be possible to find inhibiters capable of controlling the initiation and/or the establishment of C. difficilein the infected sites.

Keywords: Anthrax, Bacillus anthracis, Clostridium difficile, Spore surface, capsule, toxins, sortases, poly-glutamate, in vivo bioluminescence, regulation, bicarbonate, immunity

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  Publications

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)

Matamouros, S., England, P., and B Dupuy. 2007. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol. Microbiol. 64: 1274-1288. (PMID: 17542920)

Piris-Gimenez, A., J.-P. Corre, G. Jouvion, T. Candela, H. Khun, and P.L. Goossens. 2009. Encapsulated Bacillus anthracis interacts closely with liver endothelium. J. Infect. Dis. 200: 1381-1389. (PMID: 19785525)

van Schaik W., A. Château, M.A. Dillies, J.Y. Coppée, A.L. Sonenshein, and A. Fouet. 2009. The global regulator CodY regulates toxin gene expression in Bacillus anthracis and is required for full virulence. Infect. Immun. 77: 4437–4445. (PMID: 19651859)

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)





Activity Reports 2009 - Institut Pasteur
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