Descrizione del progetto
Il ruolo del microbiota intestinale nello sviluppo del sistema immunitario
Il microbiota intestinale è un complesso di microrganismi presenti nell’intestino che vengono acquisiti nelle prime fasi di vita e partecipano allo sviluppo del sistema immunitario. Una ricerca recente ha rivelato il verificarsi di uno stato di infiammazione transitoria dell’intestino, la «reazione allo svezzamento», nelle prime fasi della vita dei topi in risposta alla rapida diversificazione del microbiota intestinale. Il microbiota e i suoi metaboliti in questo stato di svezzamento inducono un sottotipo di cellule T regolatrici dell’intestino, che regolano la reattività immunitaria per tutto il resto della vita di un individuo. Il progetto IMPRINT, finanziato dall’UE, chiarirà il ruolo svolto dal microbiota intestinale nelle prime fasi di vita del sistema immunitario e metterà in evidenza il suo significato per la predisposizione all’infezione e alle patologie immunitarie, come le allergie e la colite, nelle fasi successive della vita.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
75724 Paris
Francia