Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease, in which infections are considered to play a pathogenic role, and more recent work is suggesting a role for the commensal flora as well, but the molecular culprits are still to be discovered. Bacterial biofilms are multicellular bacterial communities, abundant in the human microbiome, and also important in the establishment of chronic infection by pathogens. No study has yet addressed whether molecular complexes present in biofilms contribute to SLE progression. We have recently found that bacterial and also eukaryotic DNA is incorporated into curli fibers, functional bacterial amyloids present in Salmonella and E. coli biofilms. We found that curli/DNA complexes in biofilms activate conventional dendritic cells leading to production of pro-inflammatory cytokines, including Type I interferons, which are pathogenic in SLE. In vivo injection of curli/DNA complexes activated DCs and B cells, indicating that curli are a new class of composite danger signals. Administration of curli/DNA complexes triggered autoantibodies production in lupus-prone NZBxW/F1 mice and also in wild type mice, suggesting curli/DNA complexes from biofilms as novel players in SLE pathogenesis. To translate our finding to the bedside, we developed a new ELISA to measure anti-curli antibodies and found that SLE patients have high levels of anti-curli antibodies during clinical flares. We propose to explore if curli/DNA affect two major pathogenic steps in lupus: 1) the stimulation of IFN Signature by pDCs and 2) the activation of autoreactive B cells, by studying curli ability to directly activate B cells, possibly through TLRs, to act as an adjuvant to induce Ag-specific responses and break tolerance to stimulate a lupus autoAb profile. The Preliminary result that infection by a commensal E. coli induces autoAbs only when bacteria expressed curli, provides a strong rationale for studying curli as the dominant molecular stimulus by infections in lupus pathogenesis. We will test if curli is the main mediator of the pro-autoimmune effects of infections in accelerating lupus onset and inducing flares. These studies will use murine models. To establish a powerful pathogenic link with the human disease, and supported by our Preliminary results, we will also study human samples to determine whether SLE patients are exposed to curli more than healthy controls by measuring serum titers of anti-curli antibodies, in correlation with disease activity and occurrence of flare. These studies may provide a novel biomarker of flares and suggest targeting biofilms and bacterial amyloids as new therapeutic tools in lupus.
Our studies aim to discover novel players in the pathogenesis of Systemic lupus erythematosus (SLE). Using murine models and samples from SLE patients, we propose to determine the pathogenic role of components of the bacterial biofilms, the amyloid curli, and test whether infections with curli-expressing bacteria are major pathogenic stimuli and novel biomarkers of lupus flares. This project will provide cellular and molecular mechanisms for the contribution of enteric infections, and possibly the microbiome, in the pathogenesis of SLE, and a potential molecular target for treatment of autoimmunity.
| Tursi, Sarah A; Lee, Ernest Y; Medeiros, Nicole J et al. (2017) Bacterial amyloid curli acts as a carrier for DNA to elicit an autoimmune response via TLR2 and TLR9. PLoS Pathog 13:e1006315 |
