Description du projet
Caractérisation des anticorps largement neutralisants contre les agents pathogènes humains
Le projet BROADimmune, financé par le CER, vise à découvrir les mécanismes moléculaires impliqués dans la production d’anticorps puissants et largement neutralisants contre les agents pathogènes, ainsi que les facteurs limitant leur production en réponse à une infection ou à une vaccination. Des anticorps clonalement apparentés à différents sites de l’hémagglutinine de la grippe seront isolés à partir de donneurs en utilisant des cribles cellulaires à haut débit pour reconstituer leurs voies de développement. Cette approche expliquera le rôle des mutations somatiques dans la maturation des affinités et la diversification intra-clonale. L’application de la cristallographie et de la simulation de la dynamique moléculaire permettra de comprendre comment les mutations affectent l’affinité et la spécificité des anticorps. Enfin, l’analyse de la réponse anticorps aux érythrocytes infectés par Plasmodium falciparum permettra d’identifier les facteurs impliqués dans la réponse aux parasites au stade sanguin. Ces résultats auront des répercussions sur le développement d’anticorps à large spectre et sur la conception de vaccins.
Objectif
The overall goal of this project is to understand the molecular mechanisms that lead to the generation of potent and broadly neutralizing antibodies against medically relevant pathogens, and to identify the factors that limit their production in response to infection or vaccination with current vaccines. We will use high-throughput cellular screens to isolate from immune donors clonally related antibodies to different sites of influenza hemagglutinin, which will be fully characterized and sequenced in order to reconstruct their developmental pathways. Using this approach, we will ask fundamental questions with regards to the role of somatic mutations in affinity maturation and intraclonal diversification, which in some cases may lead to the generation of autoantibodies. We will combine crystallography and long time-scale molecular dynamics simulation to understand how mutations can increase affinity and broaden antibody specificity. By mapping the B and T cell response to all sites and conformations of influenza hemagglutinin, we will uncover the factors, such as insufficient T cell help or the instability of the pre-fusion hemagglutinin, that may limit the generation of broadly neutralizing antibodies. We will also perform a broad analysis of the antibody response to erythrocytes infected by P. falciparum to identify conserved epitopes on the parasite and to unravel the role of an enigmatic V gene that appears to be involved in response to blood-stage parasites. The hypotheses tested are strongly supported by preliminary observations from our own laboratory. While these studies will contribute to our understanding of B cell biology, the results obtained will also have translational implications for the development of potent and broad-spectrum antibodies, for the definition of correlates of protection, and for improving vaccine design.
Champ scientifique
- natural sciencesbiological sciencesgeneticsDNA
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesinfluenza
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesmathematicspure mathematicsmathematical analysisfunctional analysis
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
6500 Bellinzona
Suisse