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 and the World Health Organization Collaborative Center for Research on Enteroviruses and viral vaccines.
The Bordetella team (Mathilde Arrivé, Valérie Caro, David, Foureau, Laurent Guillemot, Nicole Guiso, Elisabeth Njamkepo, Guillaume Soubigou, Laurence Ormières) 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 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 2004 were the observation of the duplication of the structural gene encoding one of the major toxin of Bordetella pertussis in some clinical isolates, the confirmation that bordetella are bacteria able to invade epithelial cells but unable to replicate inside the cells and that Bordetella pertussis, agent of whooping cough, is able to induce nosocomial infections.
The enterovirus team (Jean Balanant, Stéphane Chevaliez, Francis Delpeyroux, Sophie Guillot, Céline Perret, Franck Riquet) studies the polymorphism of these viruses, the mechanisms that lead to this polymorphism and the subsequent repercussions in terms of pathogenicity and virus-host cells interactions. Recent studies contribute to increase our knowledge about RNA virus evolution with the discovery and characterisation of Coxsackievirus strains that exchange genetic material with poliovirus (in collaboration with the Pasteur Institute of Madagascar). Moreover, studies about the interaction between epidemic echovirus strains and their target cells have allowed to precise some important aspect of the complex process (cellular receptors or co-receptors) that takes place in the early steps of the viral infection.
The team of Protein and Antibody Engineering (Hugues Bedouelle, Florence Hardy, Olesia Lisova, Elodie Monsellier, Agathe Urvoas-Cisse) is studying the relations between the three-dimensional structure of proteins, their conformational stability and their mechanism of action, at the molecular and atomic levels. Its present research concerns the mechanisms of neutralization of infectious agents by antibodies, and their implications for the development of diagnostic tools and therapeutic molecules against the dengue and whooping-cough diseases. During the past year, we have mapped the paratope of an antibody that neutralizes the 4 serotypes of the dengue virus, and found that its diversity and junction residues constitute hot-spots of binding energy. We have shown that its epitope is discontinuous on the surface of the viral envelope protein. We have also shown that the stability of antibody variable fragments and the properties (sensitivity, dynamic interval) of reagentless fluorescent biosensors that are derived from them, can be strongly improved by molecular design.
The Human Population Genetics team (Lluis Quintana-Murci, Luis Barreiro, Etienne Patin, Blandine Massonnet, Francesca Luca) 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. The main results of 2004 have been the definition of the genetic architecture of populations located in the Middle East and South Asia and the evaluation of how cultural forces shape the patterns of variability of human populations. These studies put the demographic baseline to eventually identify the extent to which natural selection has shaped the evolution of a number of innate immunity genes. In addition, we have shown that the patterns of genetic variability of DC-SIGN, which attaches a number of pathogens, suggest that this gene has been under a strong selective constraint during human evolution.
Keywords: Whooping cough, poliomyelitis, dengue, vaccine, immunity, genetic diversity, human evolution