Description du projet
Rôle du microbiote intestinal dans le développement du système immunitaire
Le microbiote intestinal est un complexe de micro-organismes intestinaux acquis au début de la vie, qui participe au développement du système immunitaire. Des recherches récentes ont révélé qu’un état inflammatoire intestinal transitoire, la «réaction de sevrage», se produit chez les souris au début de leur vie en réponse à la diversification rapide du microbiote intestinal. Le microbiote et ses métabolites dans cet état de sevrage induisent un sous-type de lymphocytes T régulateurs intestinaux, qui régulent la réactivité immunitaire pour le reste de la vie. Le projet IMPRINT, financé par l’UE, élucidera le rôle du microbiote intestinal dans le système immunitaire au début de la vie et son importance pour la prédisposition aux infections et aux immunopathologies, telles que les allergies et les colites, plus tard dans la vie.
Objectif
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.
Champ scientifique
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
75724 Paris
France