Descripción del proyecto
La función de la microflora intestinal en el desarrollo del sistema inmunitario
La microflora intestinal, un complejo de microorganismos intestinales adquiridos en los primeros años de vida, participa en el desarrollo del sistema inmunitario. Investigaciones recientes han demostrado que, en ratones, se produce un estado inflamatorio intestinal transitorio, la «reacción de destete», durante los primeros años de vida en respuesta a la rápida diversificación de la microflora intestinal. La microflora y sus metabolitos en este estado de destete inducen un subtipo de linfocitos T reguladores intestinales, que controlan la respuesta inmunitaria a lo largo de la vida. El equipo del proyecto IMPRINT, financiado con fondos europeos, dilucidará la función de la microflora intestinal en el sistema inmunitario en los primeros años de vida, así como su importancia para la susceptibilidad a infecciones e inmunopatías, como alergias y colitis, a lo largo de la vida.
Objetivo
Humans acquire a complex community of intestinal microorganisms in early life (gut microbiota), which helps development of the immune system, and which may reduce risk of inflammatory disease. However, these complex microbiota-immune interactions in early life are underexplored and their subsequent influence on susceptibility to infection remains unknown. The Eberl lab recently reported that a temporary intestinal inflammatory state, termed the ‘weaning reaction’, occurs in mice during a specific window in early life (2-4 weeks) in response to the rapid diversification of the gut microbiota. During weaning, the gut microbiota and its metabolites induce a sub-type of T regulatory cells in the intestine (RORγt+ Tregs) which mediate immune tolerance throughout life. Suppression of the microbiota-induced weaning reaction suppresses RORγt+ Tregs and heightens susceptibility to immunopathology such as allergy and colitis in adulthood. However, it is unknown how the weaning reaction influences the later susceptibility and response to infection. IMPRINT will investigate how the gut microbiota influences the immune system in early life to regulate the response to infection in adulthood. Using mice, this project will evaluate the impact of suppressing the weaning reaction on susceptibility to Citrobacter rodentium infection in adulthood. Next, Treg depletion models will be used to examine whether microbiota-induced Tregs during weaning influence susceptibility to C. rodentium infection in adulthood. Finally, metagenomics, metabolomics and add-back experiments will be performed to identify specific bacteria or metabolites that promote induction of Tregs during weaning and modulate subsequent susceptibility to C. rodentium infection. By combining my skills in metagenomics and metabolomics with the host lab’s expertise in intestinal immunology, IMPRINT poses potential to uncover insights into early-life microbiota-immune interactions and the pathogenesis of infectious disease.
Ámbito científico
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
75724 Paris
Francia