Unit: Molecular Prevention and Therapy of Human Diseases

Director: Nicole GUISO

Research on vaccine preventable diseases is one of the major theme of our department "Ecosystems and Epidemiology of Infectious Diseases". 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 Center of Reference for Whooping Cough and other bordetellosis http://www.pasteur.fr/sante/clre/cadrecnr/bordet-index.html and the World Health Organization Collaborative Center for Research on Enteroviruses and viral vaccines.

The Bordetella team (Valerie Bouchez, Delphine Brun, Valérie Caro, Laurent Guillemot, Nicole Guiso, Elisabeth Njamkepo, Guillaume Soubigou) studies the bacterial determinants involved in the pathogenicity of the bacteria from the Bordetella genus, the regulation of the expression of these determinants, the immune responses that they induce in the host human or animal after infection or vaccination, the spatio-temporal evolution of the bacteria and the development of new prevention, therapeutical and diagnostic tools for the diseases they induce. The important results of 2005 were the demonstration of the absence of toxicity of B. pertussis and B. parapertussis clinical isolates towards tracheal epithelial cells in contrast to clinical isolates of B. bronchiseptica; the temporal evolution of B. pertussis population with an homogeneity of the isolates circulating in Europe and no relationship between vaccine strategy and characteristics of the isolates; a very high homogeneity of the B. parapertussis isolates; a similar duration of acellular pertussis and whole-cell pertussis vaccines induced immunity; the confirmation of the protective properties of specific anti-toxine and anti-adhesin antibodies in the animal model and the development of a real time PCR to diagnose B. pertussis and parapertussis infections.

The enterovirus team (Jean Balanant, Claire Blanchard, Francis Delpeyroux, Sophie Guillot, Sophie Jegouic, Viviane Morel) studies the genetic plasticity of these viruses, the mechanisms that lead to this plasticity and the subsequent repercussions in terms of virulence, virus-host cells interactions and pathogenicity. Our studies contribute to increase our knowledge about RNA virus evolution with the characterisation of the Coxsackievirus strains that exchange genetic material with the oral vaccine poliovirus strains (in collaboration with the Pasteur Institute of Madagascar). Recent results point out that inter-specific genetic recombination is a common mechanism of genetic plasticity at least for the viruses that are phylogenetically closely related to poliovirus and that this mechanism contributes to the genetic and also phenotypic diversity of these viruses. It could contribute to the emergence of new pathogenic viral strains.

The team of Protein and Antibody Engineering (H. Bedouelle, K. Darbandi-Tehrani, O. Lisova, E. Litzler, E. Monsellier, A. Urvoas-Cisse) studiesthe 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 monoclonal antibody and the envelope glycoprotein gpE of the dengue virus. This characterization has shown the existence of a relation between the affinities of the antibody and its efficacies of neutralization for the 4 viral serotypes. The fine mapping of its epitope, that we found discontinuous, and of its paratope by directed mutagenesis enabled us to explain and manipulate the differences of recognition for the 4 viral serotypes and the absence of recognition towards the other flaviviruses. It suggested a mechanism of neutralization. We have undertaken to equalize the affinities of this antibody towards the 4 viral serotypes by in vitro directed evolution and transform it into an efficient therapeutic molecule. In addition, we have shown that the stability of antibody variable fragments can be strongly improved by molecular design and dissected the mechanisms of this stabilization.

The "Human Population Genetics" team (Lluis Quintana-Murci, Luis Barreiro, Etienne Patin, Paul Verdu, Christine Harmant) aims to study the different forces (selective, demographic, genomic,…) shaping the patterns of variability of the human genome, with an emphasis on genes involved in the innate immune response. In 2004, we have provided genetic evidence that DC-SIGN has been under a strong selective constraint preventing accumulation of any amino acid changes over time, whilst L-SIGN has been shaped by the action of balancing selection in non-African populations. Our data point to the neck-region as the functional target of such selective pressures: CD209 present a constant size in the neck-region populationwide, while CD209L presents an excess of length variation particularly in non-African populations. In addition, we carried out an association study in a South African cohort in order to test whether polymorphisms in DC-SIGN are associated with susceptibility to tuberculosis. We found an association between two DC-SIGN promoter variants and decreased risk of developing tuberculosis.

Keywords: whooping cough, poliomyelitis, dengue, vaccines, human genetics, innate immunity

Activity Reports 2005 - Institut Pasteur

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