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Immunological and Microbiota Priming of the Response to Infection

Project description

Role of gut microbiota in immune system development

The gut microbiota is a complex of intestinal microorganisms acquired in early life, which participate in the development of the immune system. Recent research revealed that a transient intestinal inflammatory state, the ‘weaning reaction’, occurs in mice in early life in response to rapid diversification of the gut microbiota. The microbiota and its metabolites in this weaning state induce a sub-type of intestine T regulatory cells, which regulate immune reactivity for the rest of one’s life. The EU-funded IMPRINT project will elucidate the role of the gut microbiota in the immune system in early life and its significance for susceptibility to infection and immunopathologies, such as allergies and colitis, later in life.

Objective

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.

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Coordinator

INSTITUT PASTEUR
Net EU contribution
€ 196 707,84
Address
Rue du docteur roux 25-28
75724 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Other funding
€ 0,00