Descripción del proyecto
Caracterización de anticuerpos ampliamente neutralizantes contra agentes patógenos humanos
El equipo del proyecto BROADimmune, financiado por el Consejo Europeo de Investigación, pretende descubrir los mecanismos moleculares que intervienen en la generación de anticuerpos potentes y ampliamente neutralizantes contra agentes patógenos, así como los factores que limitan su producción en respuesta a la infección o la vacunación. Los anticuerpos relacionados con clones de diferentes sitios de la hemaglutinina de la gripe se aislarán de donantes utilizando cribas celulares de alto rendimiento para reconstruir sus vías de desarrollo. Este método explicará el papel de las mutaciones somáticas en la maduración de la afinidad y la diversificación intraclonal. La aplicación de técnicas de cristalografía y simulación de dinámica molecular permitirá comprender cómo afectan las mutaciones a la afinidad y la especificidad de los anticuerpos. Por último, el análisis de la respuesta de los anticuerpos a los eritrocitos infectados por «Plasmodium falciparum» permitirá identificar los factores que intervienen en la respuesta a los parásitos hemáticos. Los resultados tendrán implicaciones en el desarrollo de anticuerpos de amplio espectro y el diseño de vacunas.
Objetivo
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.
Ámbito científico
- 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
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
6500 Bellinzona
Suiza