Molecular Prevention and Therapy of Human Diseases - URA CNRS 3012  

  HEADDr Nicole GUISO /
  MEMBERSLanglais, Laurence ( / Veillault, Sophie (50%) (
GUISO Nicole, chef d'unité, chef de laboratoire, Director of the Reference National Centre of Whooping cough and others bordetelloses and of the Reference National Centre of Toxinogenic Corynebacteria, HDR ; / BEDOUELLE Hugues, Directeur de Recherche au CNRS, Directeur de l'URA3012, HDR ;
BRIENT-LITZLER Elodie PhD student - Paris VI - until 01/2009 / OULD ABEIH Mohamed Master 2 - Paris VI - until 06/2009 / BERTINE Mélanie Master 2 - Paris VI - until 06/2008
BOUCHEZ Valérie - IP Engineer (0.80 %) on contract - / GUILLOT Sophie – IP Engineer on contract – / NJAMKEPO Elisabeth– IP Engineer (50% Research - 50 % RNC) – / ROSSO Marie-Laure, cadre administratif et technique IP, Vice-director of the Reference National Center of whooping cough and others bordetelloses ; / BRUN Delphine - IP Technician (50% Research - 50 % RNC) - / DORE Gregory – IP Technician (50% Research - 50 % RNC) – / LAURENT Emilie - Technician on contract - / ROUILLON Cecile - Technician on contract- / ZIDANE Nora - IP Technician on contract - / POURADIER Nadine – Aide de laboratoire (50%) – / BELHASSEN Chantal - Aide de laboratoire (50%) – / SIMONEAU Elsa - Aide de laboratoire (50%) - / NGUYEN Huu Huan– Agent de laboratoire (50%) -

  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 theNational Centre of Reference for toxinogenic corynebacteria

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. The results of 2008 were the influence of herd immunity, induced by vaccination with whole cell pertussis vaccine, in the control of B. pertussis isolates similar to vaccine strains. The remaining isolates possess less genetic material but a higher number of Insertion Elements, leading to deletion of genes, but are as virulent as the isolates circulating before introduction of vaccination. The introduction of acellular vaccines targeting virulence should lead to the control of all types of B. pertussisisolates. The coryne team has initiated researches on the development of typing techniques of the three Coryne species that can be toxigenic (diphtheriae, ulceransand pseudotuberculosis). 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 site-directed mutagenesis of the antibody and viral envelope protein, determination of the crystal structures of the four complexes at high resolution (coll. with J. Cockburn and F. Rey), and transplantation of the epitope in the envelope protein of unrelated flaviviruses. We have shown that the epitope was specific for the taxonomic group of the dengue viruses and that it overlapped residues involved in infection. We have developed a novel ELISA assay for the early serology of infections by flaviviruses, which is simpler than the existing assays and for which all the reagents can be produced in bacteria at low levels of biosafety. We have evaluated this assay for the four serotypes of dengue virus and yellow fever virus with the serums of infected patients, and shown that it was specific of the viral group and type (coll. with Ph. Dussart).We have contributed to the development of a hybrid measle-dengue vaccine. We have shown that the affinity, stability and human tolerance of recombinant antibodies, e. g. neutralizing the anthrax toxin, can be increased by novel methods of in-vitro directed evolution or molecular design (coll. with Ph. Thullier). Finally, we have extended the design and construction of reagentless fluorescent biosensors, previously developed for recombinant antibodies, to an artificial family of antigen binding proteins, whose physico-chemical properties (production, solubility, stability) are more favorable.

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


Patents: Bedouelle, H. & Brient-Litzler, E. (19/03/2008). Reagentless fluorescent biosensors comprising a designed ankyrin repeat protein module and methods of their design and use. Application No EP08290262.8; date of priority, 19/03/08; applicants: Institut Pasteur, CNRS

Bedouelle, H. & Brient-Litzler, E. (31/07/2008). Rational design methods to create reagentless fluorescent biosensors using designed ankyrin repeat proteins. Application No EP08290742.9; date of priority, 31/07/2008; applicants: Institut Pasteur, CNRS.

Bedouelle, H., Brient-Litzler, E., Dussart, P., Despres, P. & Bremand, L. (18/12/2008) Method for the diagnosis or the screening of an arbovirus infection, reagents useful in said method and their applications. Publication No: WO2008152528 (A2); date of priority 15/06/2007; applicants: CNRS, Institut Pasteur.

List of the five publications in the four last years :

BOUCHEZ V, CARO V, LEVILLAIN E, GUIGON G, GUISO N. Genomic content of Bordetella pertussis clinical isolates circulating in areas of intensive children vaccination. PLOS ONE (2008) 3(6): e2437

GUISO N, DE LA ROCQUE F, NJAMKEPO E, LECUYER A, LEVY C, ROMAIN O, THOLLOT F, ABITBOL V, SOUBEYRAND B, COHEN R and the French pediatric group ACTIV and AFPA. Pertussis surveillance in Private Pediatric Practices, France, 2002-2006. Emerg. Inf. Dis. (2008) 14(7): 1159-1161

GUISO N, NJAMKEPO E, VIE LE SAGE F, ZEPP F, MEYER CU, ABITBOL V, CLYTI N, S CHEVALLIER. Long-term humoral and cell-mediated immunity after acellular pertussis vaccination compares favourably with whole-cell vaccines 6 years after booster vaccination in the second year of life. (2007) Vaccine. 25(8):1390-1397

LAFFLY, E., PELAT, T., CÉDRONE, F., BLÉSA, S., BEDOUELLE, H. & THULLIER P.. Improvement of an antibody neutralizing the anthrax toxin by simultaneous mutagenesis of its six hypervariable loops. (2008) J. Mol. Biol., 378, 1094-1103. PMID: 18423488; doi:10.1016/j.jmb.2008.03.045.

PELAT, T., BEDOUELLE, H., REES, A; R., CRENNELL, S. J., LEFRANC, M.-P. & THULLIER, P.. Germline humanization of a non-human primate antibody that neutralizes the anthrax toxin, by in vitro and in silico engineering. (2008)J. Mol. Biol., 384, 1400-1407. PMID: 18976662; doi: 10.1016/j.jmb.2008.10.033.

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Activity Reports 2009 - Institut Pasteur
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