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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 : Awaiting Publication