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Pasteur MLST: Institut Pasteur genomic taxonomy database of microbial strains

- The Institut Pasteur genomic taxonomy database of microbial strains (“Pasteur MLST”) is a free, publicly-accessible resource that hosts nucleotide sequence-based definitions of microbial strains, along with information on bacterial isolates (provenance data) and their genomic sequences. The Pasteur MLST database provides universal nomenclatures that are largely adopted for important pathogens (Klebsiella, Listeria, …), and represent a unifying language on strains for microbial population biology. - Unified strain taxonomies facilitate the coordinated international surveillance of bacterial pathogens. Several hundred research laboratories and public health agencies worldwide have deposited novel strain types, sequences and provenance data on their bacterial isolates. - Pasteur MLST is powered by the Open source GPL3 BIGSdb web application developed at Oxford University (Keith Jolley & Martin Maiden). ( ). Its evolution in terms of functionality is tightly linked to the developments of the software at Oxford U. Its evolution in terms of contents is managed by dedicated international teams of curators for each bacterial pathogenic species, coordinated by the PasteurMLST team. - The genomic taxonomies hosted at Pasteur MLST represent unique, authoritative resources that are highly valued by the community, as testified by the routine use of Pasteur MLST strain tags (e.g., K. pneumoniae ST258) in the scientific literature. Several labs (National Reference Centers or Units) of Institut Pasteur are coordinating the curation of genomic taxonomies (Klebsiella, Listeria, Corynebacteria, Bordetella, Leptospira, Yersinia, ...). The aim of the project is to obtain support from the C3BI HUB for the maintenance of the BIGSdb instance at Pasteur: deployment, upgrades, installation of API functionality developed by our partner, coping with future IT evolutions, ...

Project status : In Progress

Etude de la réponse immunitaire néonatale dans la coqueluche maligne : approche transcriptomique

Project status : Pending

SNP based analysis of French Bordetella pertussis isolates: comparison of isolates producing all the vaccine antigens to isolates producing only some of them.

Whooping cough is a vaccine-preventable disease due to Bordetella pertussis. Even if vaccination has allowed the control of the disease, isolates are still circulating and cyclic increases of incidence are observed every 3 to 5 years even in vaccinated countries. Most developed countries now use acellular vaccines containing 3 to 5 vaccine antigens (pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN) fimbrial proteins (FIM2/FIM3)) that have replaced whole cell vaccines. In regions vaccinating with acellular vaccines with a high coverage, isolates no more producing some vaccine antigens (mainly PRN) have been reported in the last years.   Bordetella pertussis reference genome has been fully annotated in 2003 by the Sanger Institute. Analysis and comparison of different B.pertussis genomic sequences showed that circulating B.pertussis isolates differ from vaccine and reference strains. Genome evolution is characterized by gene deletions, antigenic divergences, SNP accumulations…Recent genomic analysis gathering isolates from different countries showed that the worldwide B. pertussis population has evolved in the last 60 years,. Gene categories under selection were identified underlying that Bvg-activated genes and genes coding for surface-exposed proteins were important for adaptation. However these analyses concerned only overall vaccine antigen producing isolates.   The PTMMH Unit includes the National Center of reference for Bordetellosis. In the last years some particular B.pertussis French isolates no more producing PRN but also FHA or PT have been collected, analyzed and sequenced. We would like to further analyze these genomic data with a focus on the vaccine antigen deficient isolates through a SNP-based comparison of these isolates vs co-circulating isolates producing all vaccine antigens and vs a reference strain.

Project status : Closed

Bioinformatic analysis of the adenylate cyclase CyaA toxin

The adenylate cyclase (CyaA) produced by B. pertussis, the causative agent of whooping cough, is one of the major virulence factors of this organism. CyaA plays an important role in the early stages of respiratory tract colonization by B. pertussis. This toxin uses an original intoxication mechanism: secreted by the virulent bacteria, it is able to invade eukaryotic target cells through a unique but poorly understood mechanism that involves a direct translocation of the catalytic domain across the plasma membrane. CyaA is a 1706-residue long protein organized in a modular fashion. The ATP-cyclizing, calmodulin-activated, catalytic domain (ACD) is located in the 400 amino-terminal residues. Once secreted by the bacteria, the toxin binds calcium in the extracellular milieu and refolds into a functional state. Then, CyaA translocates its catalytic domain directly across the plasma membrane from the extracellular medium to the host cell cytoplasm where, upon activation by endogenous calmodulin, it increases the concentration of cAMP to supraphysiological levels that ultimately leads to the cell death. Recently, we succeeded to refold CyaA in a stable and monomeric form that is fully folded and functional (at variance with all prior procedures in which the polypeptides were largely aggregated upon urea removal). Both calcium and molecular confinement are mandatory to produce the monomeric state and CyaA acylation also strongly contributes to the refolding process. We further show that the monomeric preparation displayed hemolytic and cytotoxic activities suggesting that the monomer is the genuine, physiologically active form of the toxin. Hence, despite recent advances in the understanding of CyaA, its mechanisms of cell intoxication process, in particular the membrane translocation step, remains poorly understood from a fundamental perspective. The description of the molecular events occurring prior to and during the translocation of the catalytic domain across the lipi

Project status : Closed

Implémentation d’un algorithme rapide de génotypage cgMLST

Le génotypage MLST (Multi-Locus Sequence Typing) est une technique standard qui permet une caractérisation génotypique précise et reproductible des souches bactériennes. Elle consiste à déterminer la séquence nucléotidique de différents gènes répartis dans le génome (généralement entre 5 et 10). L’Institut Pasteur développe depuis de nombreuses années des schémas MLST pour différentes souches d’intérêt biomédical (e.g. Bordetella, Klebsiella, Listeria, Escherichia, Salmonella). Ces schémas consistent en la définition des différents loci et, pour chacun d’entre eux, en l’identification des allèles observés dans les différentes souches isolées (cf. Ainsi, en pratique, le génotypage d’une nouvelle souche s’effectue en déterminant le numéro de l’allèle observé au sein de son génome pour chaque locus du schéma MLST associé. Plus récemment, cette approche de classification de souches a été étendue à l’ensemble des gènes communs aux différents génomes d’une espèce donnée (i.e. core-gene) afin d’observer une meilleure discrimination entre souches proches (e.g. issues d’un même foyer épidémiologique). Ce nouveau système de typage cgMLST (core-gene MLST) s’articule ainsi sur un nombre beaucoup plus important de loci que l’approche MLST standard (e.g. plusieurs centaines ou milliers de loci, chacun contenant entre une dizaine et une centaine d’allèles). L’apparition des nouveaux schémas cgMLST implique en pratique des temps calculs relativement importants lorsque plusieurs centaines de génomes doivent être génotypés en même temps. Malheureusement, les solutions bioinformatiques actuellement disponibles pour déterminer l’ensemble des allèles à partir d’un génome assemblé s’articulent uniquement sur des recherches de type BLAST (e.g. LOCUST ; mlst), alors que de nouveaux algorithmes rapides sont actuellement développés mais uniquement pour effectuer cette tâche à partir de fichiers de reads séquencés (e.g. MentaLIST ; stringMLST). Or, l’utilisation de recherches BLAST pour déterminer les occurrences exactes d’un ensemble de séquences nucléotidiques pré-déterminées n’est trivialement pas la solution la plus optimale. Ainsi, dans le contexte actuel où le séquençage et l’assemblage de centaines de génomes bactériens est devenu routinier, il serait utile et pertinent de disposer de l’implémentation d’un algorithme très rapide de recherche des occurrences exactes d’un très grand nombre de séquences alléliques au sein d’un génome. Un tel logiciel permettrait d’accélérer significativement les missions de surveillance épidémiologique (Bordetella pertussis, mais également Klebsiella pneumoniae et Corynebacterium diphteriae) au sein de l’unité BEBP (Biodiversité et Epidémiologie des Bactéries Pathogènes), mais permettrait également de faciliter certaines analyses bioinformatiques basées sur la recherche exacte d’un grand nombres de motifs nucléotidiques au sein d’un génome.

Project status : Closed