Molecular Prevention and Therapy of Human Diseases - URA CNRS 3012, GDR 3048 CNRS  


  HEADDr Nicole GUISO / nicole.guiso@pasteur.fr
  MEMBERSLanglais, Laurence / Veillault, Sophie / GUISO Nicole/ BEDOUELLE Hugues
ABACHE Toufik / MIRANDA Frédéric / RHAYAT Lamya / OULD ABEIH Mohamed
BOUCHEZ Valérie / GUILLOT Sophie / NJAMKEPO Elisabeth / BADELL-ONCANDO Edgar / ROSSO Marie-Laure / BRUN Delphine / DORE Gregory / LAURENT Emilie / ROUILLON Cecile / ZIDANE Nora / POURADIER Nadine / DENIZON Mélanie / SIMONEAU Elsa / NGUYEN Huu Huan


  Annual Report

The main objective of our unit is to evaluate the consequences of extensive vaccination of human populations on the microbe targeted by the vaccine, the ecosystem and the human population in order to propose adapted strategies of prevention and new therapeutic tools to face some of these consequences.

Our unit harbors the National Centre of Reference for Whooping Cough and other bordetellosis http://www.pasteur.fr/sante/clre/cadrecnr/bordet-index.htmland theNational Centre of Reference for toxinogenic corynebacteria .http://www.pasteur.fr/sante/clre/cadrecnr/coryndipht-index.html

The Bordetella teamstudies the bacterial determinants involved in the pathogenicity of the bacteria from the Bordetellagenus, the regulation of the expression of these determinants, the immune responses that they induce in the host, human or animal, after infection, the spatio-temporal evolution of the bacteria and the development of new therapeutical and diagnostic tools. .Since a decade we analyze the influence of herd immunity, induced by vaccination with pertussis vaccines on the evolution of the Bordetella pertussis, the agent of whooping cough. We made the hypothesis that the immunity induced by these vaccines should lead to the control of all types of virulent B. pertussis isolates since it targets te virulence of the isolates. In 2009 we observed that B. pertussis isolates circulating in regions where the pertussis vaccine coverage is high possess a higher number of insertion elements than isolates from the pre_vaccine era and that these elements could enable the gradual elimination of the genes encoding the virulence factors. It seems that the hypothesis is confirmed since we show the emergence for the first time, in France, of isolates not expressing one of the vaccine antigen because of total elimination or inactivation in the bacterial genome of the genes encoding these factors.

The coryne teamhas developed MLST typing technique to analyse Corynebacterium diphtheria&e isolates to replace the ribotyping technique more fastidious and ambiguous.. Teaching, training scientists from the net of the Institut Pasteur in order to create National Reference Centres involved in vaccine surveillance, help in case of epidemics and public health activities, were pursued.

The protein and antibody engineering teamis studying the mechanisms of neutralization of infectious agents by antibodies at the molecular and atomic levels, and their implications for the development of diagnostic and therapeutic tools. We have characterized the mechanisms of recognition between a neutralizing antibody and the four serotypes of dengue virus by determining the crystal structures of the four complexes at high resolution (coll. with J. Cockburn and F. Rey) and by site-directed mutagenesis. We found a relation between the affinities and neutralization potencies of this antibody for the four viral serotypes. We have developed two novel ELISA assays for the early serodiagnostic of infections by flaviviruses, which are simpler to perform and cheaper to produce than the existing assays. These assays were evaluated successfully for the dengue viruses (coll. with Ph. Dussart). The natural killer cells are an important component of the innate response to infections. We have contributed to demonstrate that the NKp44 receptor participates in the activation of the natural killer cells by the dengue and West-Nile viruses through a direct interaction with the viral envelope protein. The Respiratory Syncytial Virus (RSV) is an important pathogen of the lower respiratory track in infants. We have contributed to solve the structure of a pseudo-particle of nucleocapside by a combination of X-ray crystallography and electron cryo-microscopy (coll. with R. Tawar and F. Rey). Finally, we have extended the design and construction of reagentless fluorescent biosensors, previously developed for recombinant antibodies, to artificial families of antigen binding proteins that show very favorable physico-chemical properties.

Keywords: whooping cough, diphtheria, dengue, vaccines, consequences of vaccination, antibodies, biosensors



  Publications

GUISO N. Bordetella pertussisand pertussis vaccines. Clinical Infectious Diseases. 2009, 49(10):1565-9

BOUCHEZ V, BRUN D, CANTINELLI T, DORE G, NJAMKEPO E, GUISO N, First report and detailed characterization of B. pertussis isolates not expressingPertussis Toxin or Pertactin. Vaccine, (2009), 27(43):6034-41

BONMARIN I, GUISO N, LE FLÈCHE-MATÉOS A, PATEY O, GRIMONT PA, LEVY-BRUHL D, Diphtheria: a zoonotic disease in France? Vaccine, 2009, 27(31):4196-200

HERSHKOVITZ, O, ROSENTAL, B, ROSENBERG L A, NAVARRO-SANCHEZ ME, JIVOV S, ZILKA A, GERSHONI-YAHALOM, O, BRIENT-LITZLER, E, BEDOUELLE H, HO JW, CAMPBELL KS, RAGER-ZISMAN B, DESPRES P, PORGADOR A, NKp44 receptor mediates interaction of the envelope glycoproteins from the West Nile and dengue viruses with NK cells. Journal of Immunology, 2009, 183, 2610-2621

TAWAR, R. G., DUQUERROY, S, VONRHEIN, C, VARELA, P. F, DAMIER-PIOLLE, L, CASTAGNÉ, N, MACLELLAN, K, BEDOUELLE, H, BRICOGNE, G, BHELLA, DELÉOUËT, J.-F, REY FA. X-ray structure of a Respiratory Syncytial Virus Nucleoprotein-RNA template-like assembly. Science, (2009) 326, 1279-1283



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Activity Reports 2009 - Institut Pasteur
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