Silent flagellin in chronic inflammatory and auto-immune disease

Introduction

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.

Discovery of Silent Flagellins

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.

Hypothesis

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.

Research Objectives

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.

Investigative Approach

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:

1. Establish new genetic systems for two Lachno bacteria commonly associated with human health.
2. Perform experiments in a germ-free transgenic mouse line expressing the human TLR5.
3. Utilize human intestinal organoids to account for human-specific effects.

Expected Outcomes

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.