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Deciphering the niche adaptations of a gut commensal involved in educating the host immune system

Project description

Gut microbiota and the host immune system

The gut microbiota plays an important role in driving the postnatal maturation of the gut immune system and protecting the host from pathogens. The segmented filamentous bacteria (SFB) involved in these processes attach to the ileal epithelium using a unique pointed tip structure on their unicellular particles. SFB induce a broad pro-inflammatory immune activation enabling pathogen resistance but also exacerbating disease severity in many autoimmune models. The EU-funded NICHEADAPT project will study the adaptation of this unique commensal to its unusual niche at the epithelial surface that leads to the development of the pro-inflammatory signalling using a unique in vitro SFB–host cell co-culturing system developed by the project team. This important developmental stage of the unicellular infectious particle and its immunological consequences will be further assessed using gnotobiology.

Objective

The gut microbiota plays an integral part in driving the postnatal maturation of the gut immune system and in protecting the host from pathogens. The commensal segmented filamentous bacteria (SFB) plays a critical role in these processes through its intimate attachment to the ileal epithelium using a unique pointed tip structure on its unicellular infectious particle. SFB induces a broad pro-inflammatory immune activation, and notably a striking induction of IgA and Th17 cell responses, that fosters pathogen resistance but can also exacerbate disease severity in a number of autoimmune models, making SFB an important microbe in health and disease. SFB is found in many vertebrate species, including humans, and SFB monocolonization has allowed a detail study of its immunostimulatory potential. However, the unique and complex life-cycle of SFB and SFBs interaction with the host has remained poorly understood due to a lack of in vitro culturing techniques. We recently overcame this hurdle by establishing the first in vitro SFB-host cell co-culturing system. Using this system, unicellular SFB were discovered to be flagellated and to stimulate TLR5 signaling, revealing a missing link of immunological importance in the SFB life-cycle. This important developmental stage will now be further characterized and its immunological consequence assessed using gnotobiology. State-of-the-art microscopy techniques will be employed to characterize in detail the SFB life-cycle and novel structures discovered during in vitro growth. Unicellular SFB surface proteins will be identified using mass spectrometry, localized on the bacterium and tested for their ability to mediate host cell attachment. In addition, next generation sequencing and transcriptomics will be used to assess SFB genome evolution and SFB niche constraints. Together, this work will lead to a detailed view of the SFB life-cycle and how SFB has adapted to its unique replicative niche at the epithelial surface.

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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ERC-COG - Consolidator Grant

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Call for proposal

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(opens in new window) ERC-2019-COG

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Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 999 948,00
Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 999 948,00

Beneficiaries (1)

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