Public health studies show the necessity to develop new therapeutic strategies to combat infection. The association of comparative genomics, the analysis of the genetic diversity of strains, global transcription analysis and bioinformatics is a powerful tool to achieve this goal. Our activity is centered on the sequencing and analysis of microbial pathogens. We also use the high-density array technology for the evaluation of the expression of a large number of genes and for genome comparisons involving different strains of a bacterial species.
At present, we are involved in the analysis of the genomes of four bacteria. Listeria monocytogenes is a bacterium causing serious food-borne infections (mortality : 30 %), whose clinical signs are meningitis and abortion. The sequence and annotation of its genome (2.94 megabases) has been completed by a consortium of 10 laboratories, coordinated by us together with P. Cossart (Institut Pasteur, Laboratoire des Interactions Bactéries-Cellules). We also have completed the sequence of L. innocua, a non-pathogenic bacterium closely related to L. monocytogenes. The comparison of these two genome sequences - with the use of the software FindTarget developed in our laboratory will help us to identify potential virulence genes, and more generally, will lead to a better understanding of the pathogenicity of L. monocytogenes and its ability to contaminate food. Specific features of this bacterium have been deduced from the analysis of its genome and have been described in a recently submitted article. It contains a large number of proteins of the following families : surface proteins containing an LPXTG motif, internalins, sugar transport systems, proteins showing similarities to Bacillus subtilis competence proteins and regulators of the Crp/Fnr family. Furthermore, we are using a comparative genomics approach based on DNA arrays to characterize clinical and environmental isolates of Listeria.
Photorhabdus luminescens is a commensal of a nematode and an insect parasite. This bacterium is both a model for the study of host-parasite interactions, and potentially an industrial bacterium because of its capacity to synthetize numerous toxins (insecticides, bacteriocides and fungicides) and to secrete numerous enzymes. At present, this sequencing project is in the final stage : the genome of 5.6 megabases has been assembled into 4 contigs. In collaboration with the Laboratoire de Pathologie Comparée (INRA, Montpellier) and the company Aventis CropScience we have identified numerous genes encoding toxins.
Streptococcus agalactiae is a group B Streptococcus. Neonatal infections caused by Streptococci constitute an important health problem. The frequency of occurrence is 2.5 per 1000 births, with a rate of mortality in the range of 4 - 10%, and cases of meningitis leading to neurological aftereffects in 25 - 50 % of the cases. We have assembled this genome of about 2 megabases into 40 contigs. The availability of the complete genome sequences of two related Streptococci, S. pneumoniae and S. pyogenes, will allow us to carry out a comparative genomics study.
In the framework of our participation in the Aspergillus fumigatus genome project (see below) and for transcriptome analysis, we have sequenced 9000 genomic tags of this fungus causing invasive aspergillosis. DNA arrays are prepared to carry out studies of global gene expression in collaboration with J.-P. Latgé (Unité des Aspergillus), and to identify new targets to combat this fungus. Recently, an international project aimed at the sequencing of the Aspergillus fumigatus genome has been set up with the participation of the Sanger Centre (UK), the University of Manchester (UK), The Institute for Genomic Research (TIGR, USA), the Universities of Madrid and Salamanca (Spain), and the Institut Pasteur (Unité des Aspergillus and our laboratory).
Finally, our laboratory participates in a pilot project aimed at the sequencing of one megabase of the Dictyostelium discoideum genome, in collaboration with the Sanger Centre and the Unité de Régulation Enzymatique des Activités Cellulaires (Institut Pasteur) headed by Michel Véron.