Leaky gut drives autoimmunity via bacterial flagellin-mediated activation of TLR5

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Leaky gut drives autoimmunity via bacterial flagellin-mediated activation of TLR5 Project Summary The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of lumen contents to enter the blood stream creating a “leaky gut.” In individuals with a genetic predisposition, a leaky gut may allow commensal bacteria and/or bacterial components to enter the body and trigger the initiation and development of autoimmune disease. Systemic lupus erythematosus (SLE) is a complex autoimmune disease manifested in multiple organs. Albeit decades of investigation, the pathogenesis of SLE remains unclear. In recent years, we and others have hypothesized the presence of a leaky gut in SLE and that the leaky gut can contribute to the pathogenesis of the disease. Increased levels of bacterial lipopolysaccharide (LPS) endotoxin have been observed in the blood of both SLE patients and lupus-prone mice, supporting this hypothesis. However, it is unknown how a leaky gut can contribute to SLE initiation and/or development. While exogenous LPS has been shown to facilitate murine lupus, surprisingly, deletion of toll-like receptor 4 (TLR4, the receptor of LPS) did not attenuate disease in lupus-prone MRL/lpr mice. In this high risk-high reward proposal, we seek to investigate the role of other bacterial components that could potentially trigger systemic autoimmunity in mice genetically prone to develop lupus. In preliminary studies we discovered that significant higher levels of anti-flagellin antibodies are present in the circulation of both SLE patients and MRL/lpr mice. This indicates that the leaky gut may have allowed for translocation of flagellated bacteria and/or flagellin across the intestinal epithelium and into the circulation. Circulating flagellin as well as anti-flagellin immune complexes (formed by the antigen and its specific antibody) could potentially activate TLR5, the receptor of flagellin, to drive inflammation leading to systemic autoimmunity seen in SLE. Therefore, we hypothesize that a leaky gut leads to SLE-like autoimmunity through bacterial flagellin-mediated activation of TLR5. We propose two specific aims to test this hypothesis in MRL/lpr, a mouse model of genetically prone SLE. Aim 1 is to determine the capability of exogenous flagellin to facilitate systemic autoimmunity. Aim 2 is to demonstrate the lack of SLE development with Tlr5 deletion. Using the cutting-edge CRISPR/Cas9 technology, we aim to reveal a mechanism by which a leaky gut drives autoimmunity, and provide the scientific basis for the design of novel therapeutic approaches against SLE that target restoration of the intestinal barrier function.