Project description
Potential role of silent flagellins in immune response disruption
Flagellins are a family of proteins found in the flagella of some bacteria, including Lachnospiraceae (Lachno). Flagellins are generally potent activators of the immune system. However, a new class of flagellins – ‘silent’ flagellins – appear to bind their receptors without inducing a response. Lachno are typically associated with a healthy gut microbiome. Interestingly, patients with Crohn’s disease and myalgic encephalomyelitis can have elevated levels of antibodies to Lachno flagellins, while many Lachno species encode silent flagellins. Funded by the European Research Council, the SilentFlame project aims to explore the potential role of silent flagellins in homeostasis and in the breakdown of immune tolerance seen in chronic inflammatory and autoimmune diseases.
Objective
The last century has seen a dramatic increase in the prevalence of chronic inflammatory and autoimmune illnesses, including diseases of poorly understood etiology such as Crohn’s disease (CD) and myalgic encephalomyelitis (ME). Recent reports for CD and ME of elevated levels of antibodies against flagellins made by Lachnospiraceae (Lachno), which are usually associated with health, suggest a common breakdown of immune tolerance. My laboratory recently discovered a new class of flagellin that we termed “silent” because it binds the innate immune receptor TLR5 without inducing a response. Many Lachno species, which are highly abundant and prevalent in the human gut microbiome, encode silent flagellins. We have observed that silent flagellin is highly targeted by antibodies in CD and ME.
We hypothesize that the usage of silent flagellins by Lachnos and their reciprocal interactions with host immunity sustain inflammation in the gut and may drive auto-immunity. In SilentFlame, we will explore the breadth of the antibody response against Lachno flagellins in a panel of chronic inflammatory and autoimmune conditions, as well as potential cross-reactivity with human proteins. In parallel, we will investigate the enigmatic role of silent flagellin in bacterial colonization of the gut and host adaptive immune responses, both in homeostasis and inflammation. To do so, we will establish new genetic systems for two Lachno bacteria commonly associated with human health and perform experiments in a germfree transgenic mouse line expressing the human TLR5, as well as human intestinal organoids to account for human specific effects. This research will advance basic understanding of host-microbe reciprocal interactions in homeostasis and chronic inflammation. The knowledge gained will enable the development of targeted therapeutic strategies aimed at restoring balance and ameliorating the conditions that arise when this delicate equilibrium is disrupted.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinephysiologyhomeostasis
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Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
80539 Munchen
Germany